Bone - Articles in Press

Controversy about reference values for vertebral morphometry by X-ray absorptiometry - Corrected Proof

Daniele Diacinti, Daniela Pisani, Maria Sofia Cattaruzza — 2012-02-16

We are pleased that our paper has generated interest in the need to shed light on morphometric X-ray absorptiometry (MXA) reference values to be used in clinical practice. We have read the letter by Kanterwericz where he derived reference data from 2832 postmenopausal women aged 58–63y selected from a sample of 2968 women randomly recruited from the community after excluding women with vertebral fracture.

Stanniocalcin 2 is associated with ectopic calcification in α-klotho mutant mice and inhibits hyperphosphatemia-induced calcification in aortic vascular smooth muscle cells - Corrected Proof

2012-02-14

Abstract: Ectopic calcification of soft tissues can have severe clinical consequences especially when localized to vital organs such as heart, arteries and kidneys. Mammalian stanniocalcin (STC) 1 and 2 are glycoprotein hormones identified as calcium/phosphate-regulating hormones. The mRNA of STCs is upregulated in the kidney of α-klotho mutant (kl/kl) mice, which have hypercalcemia, hyperphosphatemia and hypervitaminosis D and exhibit a short life span, osteopenia and ectopic calcification. In the present study, we investigated the distribution and localization of STCs in kl/kl mice. Quantitative RT-PCR revealed that renal mRNA expression of STC2 was increased in both kl/kl mice and fibroblast growth factor 23 (Fgf23)-null mice compared with wild type mice. Interestingly, STC2 protein was focally localized with the calcified lesions of renal arterioles, renal tubular cells, heart and aorta in kl/kl mice. In vitro analysis of rat aortic vascular smooth muscle (A-10) cells showed that inorganic phosphate (Pi) stimulation significantly increased STC2 mRNA levels as well as that of osteocalcin, osteopontin and the type III sodium-dependent phosphate co-transporter (PiT-1), and induced STC2 secretion. Interestingly, the knockdown with a small interfering RNA or the over-expression of STC2 showed acceleration and inhibition of Pi-induced calcification in A-10 cells, respectively. These results suggest that the up-regulation of STC2 gene expression resulting from abnormal α-klotho-Fgf23 signaling may contribute to limitation of ectopic calcification and thus STC2 represents a novel target gene for cardio-renal syndrome.Highlights: ► Renal STC2 expression was increased in both kl/kl mice and FGF23-null mice. ► STC2 protein co-localized with calcified lesions of kidney, heart and aorta in kl/kl mice. ► Inorganic phosphate (Pi) stimulated STC2 expression in rat aortic vascular smooth muscle (A-10) cells. ► STC2 inhibited Pi-induced calcification in A-10 cells.

Gentamicin and bone morphogenic protein-2 (BMP-2)-delivering heparinized-titanium implant with enhanced antibacterial activity and osteointegration - Corrected Proof

Deok-Won Lee, Young-Pil Yun, Kyeongsoon Park, Sung Eun Kim — 2012-02-13

Abstract: Insufficient bonding of implants to bone tissues and bacterial infections lead to the failure of titanium (Ti)-based orthopedic and dental implants. The aim of this study is to develop novel Ti implants that enhance osteoblast functions, while simultaneously decreasing bacterial infections. First, the surface of pristine Ti was functionalized with heparin-dopamine by mimicking a mussel adhesion mechanism. Gentamicin sulfate (GS) and/or bone morphogenic protein-2 (BMP-2) was then sequentially immobilized to the heparinized-Ti (Hep-Ti) surface. The compositions of pristine Ti and Hep-Ti with or without gentamicin and/or BMP-2 were characterized by X-ray photoelectron spectroscopy (XPS) and the growth of Staphylococcus aureus on the substrates was assayed. Osteoblast functions of all Ti substrates were investigated by cell proliferation assays, alkaline phosphatase (ALP) activity, and calcium deposition. The results showed that the growth of bacteria on GS/Hep-Ti and GS/BMP-2/Hep-Ti was significantly lower compared to that on the pristine Ti and BMP-2/Hep-Ti. In addition, BMP-2/Hep-Ti and GS/BMP-2/Hep-Ti significantly enhanced ALP activity and calcium mineral deposition of osteoblast cells. Taken together, GS/BMP-2/Hep-Ti could achieve the dual functions of excellent antibacterial activity and osteoblast function promotion. Therefore, dual drug (antibiotics and osteoinductive protein)-eluting Ti substrates such as GS/BMP-2/Hep-Ti are a promising material for the enhanced osteointegration and implant longevity in orthopedics and dentistry.Graphical abstract: To develop novel Ti implants that enhance osteoblast functions, while simultaneously decreasing bacterial infections, dual drug (gentamicin and osteoinductive BMP-2)-eluting Ti substrate could achieve the dual functions of excellent antibacterial activity and osteoblast function promotion. This dual drug-eluting Ti substrate will be a promising material for the enhanced osteointegration and implant longevity in orthopedics and dentistry.Highlights: ► Gentamicin-releasing titanium substrates such as GS/Hep-Ti and GS/BMP/Hep-Ti have excellent antibacterial activity. ► BMP-2-releasing titanium substrates such as BMP-2/Hep-Ti and GS/BMP/Hep-Ti have enhanced osteoblast function. ► GS/Hep-Ti has relatively low osteoblast function, whereas BMP-2/Hep-Ti has no antibacterial activity. ► Simultaneously gentamicin and BMP-2-releasing Ti(GS/BMP/Hep-Ti) substrate have dual functions such as excellent antibacterial activity and osteoblast function promotion.

Tooth dentin defects reflect genetic disorders affecting bone mineralization - Corrected Proof

2012-02-13

Abstract: Several genetic disorders affecting bone mineralization may manifest during dentin mineralization. Dentin and bone are similar in several aspects, especially pertaining to the composition of the extracellular matrix (ECM) which is secreted by well-differentiated odontoblasts and osteoblasts, respectively. However, unlike bone, dentin is not remodelled and is not involved in the regulation of calcium and phosphate metabolism. In contrast to bone, teeth are accessible tissues with the shedding of deciduous teeth and the extractions of premolars and third molars for orthodontic treatment. The feasibility of obtaining dentin makes this a good model to study biomineralization in physiological and pathological conditions. In this review, we focus on two genetic diseases that disrupt both bone and dentin mineralization. Hypophosphatemic rickets is related to abnormal secretory proteins involved in the ECM organization of both bone and dentin, as well as in the calcium and phosphate metabolism. Osteogenesis imperfecta affects proteins involved in the local organization of the ECM. In addition, dentin examination permits evaluation of the effects of the systemic treatment prescribed to hypophosphatemic patients during growth. In conclusion, dentin constitutes a valuable tool for better understanding of the pathological processes affecting biomineralization.Highlights: ► Several genetic disorders affecting bone mineralization such as osteogenesis imperfecta and hypophosphatemic rickets, also disturb dentin mineralization. ► Dentin and bone are similar in several aspects, especially pertaining to the composition of the extracellular matrix. ► In contrast to bone, dentin is not involved in calcium phosphate metabolism and is not remodelled during life. ► Dentin examination constitutes a valuable tool for better understanding of the pathological processes affecting biomineralization. ► Dentin examination permits evaluation of the effects of the systemic treatment prescribed to hypophosphatemic patients during growth.

Factors associated with screening or treatment initiation among male United States veterans at risk for osteoporosis fracture - Corrected Proof

Richard E. Nelson, Jonathan R. Nebeker, Brian C. Sauer, Joanne LaFleur — 2012-02-10

Abstract: Male osteoporosis continues to be under-recognized and undertreated in men. An understanding of which factors cue clinicians about osteoporosis risk in men, and which do not, is needed to identify areas for improvement. This study sought to measure the association of a provider's recognition of osteoporosis with patient information constructs that are available at the time of each encounter. Using clinical and administrative data from the Veterans Health Administration system, we used a stepwise procedure to construct prognostic models for a combined outcome of osteoporosis diagnosis, treatment, or a bone mineral density (BMD) test order using time-varying covariates and Cox regression. We ran separate models for patients with at least one primary care visit and patients with only secondary care visits in the pre-index period. Some of the strongest predictors of clinical osteoporosis identification were history of gonadotropin-releasing hormone (GnRH) agonist exposure, fragility fractures, and diagnosis of rheumatoid arthritis. Other characteristics associated with a higher likelihood of having osteoporosis risk recognized were underweight or normal body mass index, cancer, fall history, and thyroid disease. Medication exposures associated with osteoporosis risk recognition included opioids, glucocorticoids, and antidepressants. Several known clinical risk factors for fracture were not correlated with osteoporosis risk including smoking and alcohol abuse. Results suggest that clinicians are relying on some, but not all, clinical risk factors when assessing osteoporosis risk.

The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women - Corrected Proof

2012-02-10

Abstract: Parathyroid hormone (PTH), currently the only marketed anabolic treatment for osteoporosis, is available as the full-length hormone, human PTH1-84, or as the human PTH1-34 fragment (teriparatide).Both must be administered as a daily subcutaneous (sc) injection. A new oral formulation of human PTH1-34 (PTH134) is being developed as a more convenient option for patients.In this single-center, partially-blinded, incomplete cross-over study, the safety, tolerability, and exposure of oral PTH134 (teriparatide combined with 2 different quantities of the absorption enhancer 5-CNAC) were assessed in 32 healthy postmenopausal women.16 subjects were randomized to receive 4 single doses out of 6 different treatments: placebo, teriparatide 20μg sc, or 1, 2.5, 5 or 10mg of oral PTH134 formulated with 200mg 5-CNAC.Subsequently, another 16 subjects were randomized to receive 4 out of 6 different treatments: placebo, teriparatide 20μg sc, or 2.5 or 5mg of oral PTH134 formulated with either 100 or 200mg 5-CNAC. Doses were given ≥6days apart.All doses of PTH134 were rapidly absorbed, and showed robust blood concentrations in a dose-dependent manner. Interestingly, PTH1-34 disappeared from blood faster after oral than after sc administration. Specifically, 2.5 and 5mg PTH134 (containing 200mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of sc teriparatide 20μg (Forsteo®).Mean+/−SD hPTH134 Cmax values were, respectively, 74+/−59, 138+/−101, 717+/−496, and 1624+/−1579pg/mL for 1, 2.5, 5, and 10mg doses of this peptide administered with 200mg 5-CNAC; while mean+/−SD AUC (0-last) values were, respectively, 30+/−40, 62+/−69, 320+/−269, and 627+/−633h*pg/mL. The corresponding estimates for teriparatide 20μg sc were 149+/−35 for Cmax and 236+/−58 for AUC (0-last)Ionized calcium remained within normal limits in all treatment groups except for 3 isolated events. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5mg: three withdrew for symptomatic hypotension (two of whom were in the 200mg 5-CNAC group), three because of delayed vomiting (two from the 200mg 5-CNAC group), one was proactively withdrawn by the investigator for symptomatic hypercalcemia (receiving 2.5mg/100mg 5-CNAC) at slightly supra-normal total calcium but normal ionized serum calcium levels. One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported.In conclusion, the study demonstrated potential therapeutically relevant PTH1-34 systemic exposure levels after oral administration of PTH1-34 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20μg sc, with a comparable incidence of AEs in healthy postmenopausal women.Highlights: ► PTH134 is an oral formulation of teriparatide. ► The single-dose exposure profile is distinct from that observed after sc teriparatide. ► High teriparatide Cmax from PTH134 did not lead to hypercalcemia. ► Observed pharmacokinetic variability might limit development potential. ► Future multiple-dose studies need to explore PK/PD relationship with bone biomarkers.

Morphometric X-ray absorptiometry (MXA) vertebral heights in Spanish women - Corrected Proof

2012-02-10

We read with interest the recent work by Diacinti and colleagues on morphometric X-ray absorptiometry (MXA) reference data for Italian women . As we are presently conducting a study on the prevalence of vertebral fractures (VF) in Spanish women using the same device, we would like to take this opportunity to compare our results with those provided by the authors. Diacinti et al. reported that, in a sample of 1254 women (mean age 63.7±11.3, range 26–88), MXA heights and ratios were significantly lower when compared with other populations (United Kingdom) but more importantly, these values were also lower than the reference values provided by the manufacturer, even after applying a normalization procedure.

Bone marrow-derived heparan sulfate potentiates the osteogenic activity of bone morphogenetic protein-2 (BMP-2) - Corrected Proof

2012-02-06

Abstract: Lowering the efficacious dose of bone morphogenetic protein-2 (BMP-2) for the repair of critical-sized bone defects is highly desirable, as supra-physiological amounts of BMP-2 have an increased risk of side effects and a greater economic burden for the healthcare system. To address this need, we explored the use of heparan sulfate (HS), a structural analog of heparin, to enhance BMP-2 activity. We demonstrate that HS isolated from a bone marrow stromal cell line (HS-5) and heparin each enhances BMP-2-induced osteogenesis in C2C12 myoblasts through increased ALP activity and osteocalcin mRNA expression. Commercially available HS variants from porcine kidney and bovine lung do not generate effects as great as HS5. Heparin and HS5 influence BMP-2 activity by (i) prolonging BMP-2 half-life, (ii) reducing interactions between BMP-2 with its antagonist noggin, and (iii) modulating BMP2 distribution on the cell surface. Importantly, long-term supplementation of HS5 but not heparin greatly enhances BMP-2-induced bone formation in vitro and in vivo. These results show that bone marrow-derived HS effectively supports bone formation, and suggest its applicability in bone repair by selectively facilitating the delivery and bioavailability of BMP-2.Highlights: ► Bone marrow-derived heparan sulfate (HS5) is an effective adjuvant of BMP-2. ► HS5 potentiates BMP-2-dependent tissue mineralization in vitro and in vivo. ► HS5 modulates BMP-2 bioavailability similar to heparin. ► Heparin enhances BMP-2 activity in short- but not long-term osteogenic differentiation.

Age-specific profiles of tissue-level composition and mechanical properties in murine cortical bone - Corrected Proof

Mekhala Raghavan, Nadder D. Sahar, David H. Kohn, Michael D. Morris — 2012-02-06

Abstract: There is growing evidence that bone composition and tissue-level mechanical properties are significant determinants of skeletal integrity. In the current study, Raman spectroscopy and nanoindentation testing were co-localized to analyze tissue-level compositional and mechanical properties in skeletally mature young (4 or 5months) and old (19months) murine femora at similar spatial scales. Standard multivariate linear regression analysis revealed age-dependent patterns in the relationships between mechanical and compositional properties at the tissue scale. However, changes in bone material properties with age are often complex and nonlinear, and can be missed with linear regression and correlation-based methods. A retrospective data mining approach was implemented using non-linear multidimensional visualization and classification to identify spectroscopic and nanoindentation metrics that best discriminated bone specimens of different age-classes. The ability to classify the specimens into the correct age group increased by using combinations of Raman and nanoindentation variables (86–96% accuracy) as compared to using individual measures (59–79% accuracy). Metrics that best classified 4 or 5month and 19month specimens (2-age classes) were mineral to matrix ratio, crystallinity, modulus and plasticity index. Metrics that best distinguished between 4, 5 and 19month specimens (3-age classes) were mineral to matrix ratio, crystallinity, modulus, hardness, cross-linking, carbonate to phosphate ratio, creep displacement and creep viscosity. These findings attest to the complexity of mechanisms underlying bone tissue properties and draw attention to the importance of considering non-linear interactions between tissue-level composition and mechanics that may work together to influence material properties with age. The results demonstrate that a few non-linearly combined compositional and mechanical metrics provide better discriminatory information than a single metric or a single technique.Highlights: ► Mechanical consequence of bone compositional changes are age-dependent. ► Difficult to assume linearity of the effects of compositional changes. ► Non-linear interdependence between these properties assessed as a function of age. ► Single measures insufficiently classify how aging manifests itself at tissue-level. ► Combined Raman and nanoindentation measures improve classification.

Modeling seasonal variation of hip fracture in Montreal, Canada - Corrected Proof

2012-02-03

Abstract: The investigation of the association of the climate variables with hip fracture incidences is important in social health issues. This study examined and modeled the seasonal variation of monthly population based hip fracture rate (HFr) time series. The seasonal ARIMA time series modeling approach is used to model monthly HFr incidences time series of female and male patients of the ages 40–74 and 75+ of Montreal, Québec province, Canada, in the period of 1993–2004. The correlation coefficients between meteorological variables such as temperature, snow depth, rainfall depth and day length and HFr are significant. The nonparametric Mann–Kendall test for trend assessment and the nonparametric Levene's test and Wilcoxon's test for checking the difference of HFr before and after change point are also used. The seasonality in HFr indicated sharp difference between winter and summer time. The trend assessment showed decreasing trends in HFr of female and male groups. The nonparametric test also indicated a significant change of the mean HFr. A seasonal ARIMA model was applied for HFr time series without trend and a time trend ARIMA model (TT-ARIMA) was developed and fitted to HFr time series with a significant trend. The multi criteria evaluation showed the adequacy of SARIMA and TT-ARIMA models for modeling seasonal hip fracture time series with and without significant trend. In the time series analysis of HFr of the Montreal region, the effects of the seasonal variation of climate variables on hip fracture are clear. The Seasonal ARIMA model is useful for modeling HFr time series without trend. However, for time series with significant trend, the TT-ARIMA model should be applied for modeling HFr time series.Highlights: ► The seasonal variation of hip fracture is associated to climate conditions. ► We model the seasonal variation of hip fracture. ► The nonparametric methods show trend in hip fracture data. ► We modeled hip fracture seasonality in the presence of trend.

The enhancement of osteogenesis through the use of dental pulp pluripotent stem cells in 3D - Corrected Proof

2012-02-03

Abstract: The potential for osteogenic differentiation of dental pulp mesenchymal stem cells (DPMSCs) in vitro and in vivo has been well documented in a variety of studies. Previously, we obtained a population of cells from human dental pulp called dental pulp pluripotent stem cells (DPPSCs) that could differentiate into mesodermal, ectodermal and endodermal progenies. We compared the osteogenic capacity of DPPSCs and DPMSCs that had been isolated from the same donors (N=5) and cultivated in the same osteogenic medium in 3D (three dimensions) Cell Carrier glass scaffolds. We also compared the architecture of bone-like tissue obtained from DPPSCs and human maxillary bone tissue. Differentiation was evaluated by scanning electron microscopy, whereas the expression of bone markers such as ALP, Osteocalcin, COLL1 and Osteonectin was investigated by quantitative real time polymerase chain reaction (qRT-PCR). We also used calcium quantification, Alizarin red staining and alkaline phosphatase (ALP) activity to compare the two cell types. New bone tissue formed by DPPSCs was in perfect continuity with the trabecular host bone structure, and the restored bone network demonstrated high interconnectivity. Significant differences between DPPSCs and DPMSCs were observed for the expression of bone markers, calcium deposition and ALP activity during osteogenic differentiation; these criteria were higher for DPPSCs than DPMSCs. Both DPPSCs and differentiated tissue showed normal chromosomal dosage after being cultured in vitro and analysed using short-chromosome genomic hybridisation (short-CGH). This study demonstrates the stability and potential for the use of DPPSCs in bone tissue engineering applications.Highlights: ► DPPSCs are capable of producing functional 3D bone-like tissue. ► DPPSCs have more potential of differentiation into bone-like tissue than DPMSCs. ► DPPSCs differentiated into trabecular and cortical bone through 3D glass scaffolding. ► The architecture achieved with DPPSCs resembles human bone structure. ► DPPSCs are genetically stable before and after the differentiation.

Murine ameloblasts are immunonegative for Tcirg1, the v-H-ATPase subunit essential for the osteoclast plasma proton pump - Corrected Proof

2012-02-02

Abstract: Maturation stage ameloblasts of rodents express vacuolar type-H-ATPase in the ruffled border of their plasma membrane in contact with forming dental enamel, similar to osteoclasts that resorb bone. It has been proposed that in ameloblasts this v-H-ATPase acts as proton pump to acidify the enamel space, required to complete enamel mineralization. To examine whether this v-H-ATPase in mouse ameloblasts is a proton pump, we determined whether these cells express the lysosomal, T-cell, immune regulator 1 (Tcirg1, v-H-Atp6v0a3), which is an essential part of the plasma membrane proton pump that is present in osteoclasts. Mutation of this subunit in Tcirg1 null (or oc/oc) mice leads to severe osteopetrosis. No immunohistochemically detectable Tcirg1 was seen in mouse maturation stage ameloblasts. Strong positive staining in secretory and maturation stage ameloblasts however was found for another subunit of v-H-ATPase, subunit b, brain isoform (v-H-Atp6v1b2). Mouse osteoclasts and renal tubular epithelium stained strongly for both Tcirg1 and v-H-Atp6v1b2. In Tcirg1 null mice osteoclasts and renal epithelium were negative for Tcirg1 but remained positive for v-H-Atp6v1b2. The bone in these mutant mice was osteopetrotic, tooth eruption was inhibited or delayed, and teeth were often morphologically disfigured. However, enamel formation in these mutant mice was normal, ameloblasts structurally unaffected and the mineral content of enamel similar to that of wild type mice.We concluded that Tcirg1, which is essential for osteoclasts to pump protons into the bone, is not appreciably expressed in maturation stage mouse ameloblasts. Our data suggest that the reported v-H-ATPase in maturation stage ameloblasts is not the typical osteoclast-type plasma membrane associated proton pump which acidifies the extracellular space, but rather a v-H-ATPase potentially involved in intracellular acidification.Highlights: ► Mouse ameloblasts are immunonegative for osteoclast proton pump subunit Tcirg1. ► Mouse osteoclasts are strongly immunopositive for Tcirg1. ► Enamel formation is unaffected in Tcirg1-null (oc/oc) mice. ► It is unlikely that ameloblasts have a proton pump as osteoclasts to acidify matrix.

Microindentation can discriminate between damaged and intact human bone tissue - Corrected Proof

E. Dall'Ara, R. Schmidt, P. Zysset — 2012-02-02

Abstract: Bone mineral density and microarchitecture was found to predict 70–95% of bone strength. Microdamage, as factor of bone quality, might help to explain the remaining uncertainties. The goal of this study was to investigate whether microindentation can discriminate between intact and severely damaged human vertebral bone tissue in vitro. One portion from each human vertebral slice (N=35) tested in compression in a previous study was embedded, polished and tested in wet conditions by means of microindentation. The indentation moduli and hardness (HV) of trabecular, osteonal and interstitial bone structural units were computed along the cranio-caudal direction. Each indented region was defined as damaged or intact as seen under a light microscope. A total of 1190 indentations were performed. While both hardness and indentation modulus were independent from gender, both mechanical properties were affected by damage and microstructure. The damaged regions showed 50% lower stiffness and hardness compared to undamaged ones. Interstitial bone was stiffer and harder (13.2±4.4GPa and 44.7±20.3HV) than osteonal bone (10.9±3.8GPa and 37.8±17.3HV), which was stiffer and harder than trabecular bone (8.1±3.0GPa and 28.8±11.2HV) indented in the transverse direction. Moreover, along the axial direction intact trabecular bone (11.4±4.3GPa) was 16% less stiff than the intact interstitial bone and as stiff as intact osteonal bone. In conclusion microindentation was found to discriminate between highly damaged and intact tissue in both trabecular and cortical bone tested in vitro. It remains to be investigated whether this technique would be able to detect also the damage, which is induced by physiological load in vivo.Highlights: ► We tested damaged and intact human vertebral trabecular and cortical bone tissue. ► We found that severe microdamage is associated with a 50% reduction of Ei and HV. ► We found that interstitial bone is stiffer than osteonal bone. ► We found that along their axial direction trabeculae are as stiff as osteons.

Strontium ranelate treatment increases osteoprotegerin serum levels in postmenopausal osteoporotic women - Corrected Proof

J.Y. Reginster, O. Bruyere, J. Collette — 2012-02-02

In the September Epub issue of BONE , Peng et al. suggested that osteoprotegerin (OPG) plays an important role in the cross-talking between osteoclasts and osteoblasts in response to strontium ranelate (SrRan) treatment. This elegant, in vitro, study confirms previous results published by the same group suggesting that OPG deficiency attenuates strontium-mediated inhibition of osteoclastogenesis and bone resorption .

A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study - Corrected Proof

2012-02-02

Abstract: The Matrilin3 gene (MATN3) encodes an extracellular matrix protein, which modulates chondrocyte differentiation. The aim of this study was to test for association of MATN3 polymorphisms with bone mineral density (BMD), fracture, vertebral fracture, bone turnover or 25-hydroxyvitamin D [25(OH)D] in postmenopausal women. A community-based population of 1488 postmenopausal women was randomly selected in Beijing. The history of fracture and vertebral fracture was obtained via questionnaire and vertebral X-ray respectively. BMD of lumbar spine (2–4), femoral neck and total hip were measured by dual energy X-ray absorptiometry. Serum N-terminal procollagen of type 1 collagen (P1NP), β-isomerized type I collagen C-telopeptide breakdown products (β-CTX) and 25(OH)D were quantified. Binary logistic regression revealed that Haplotype-4 was significantly associated with vertebral fracture risk in both additive model (p=0.023, OR=1.521) and dominant model (p=0.028, OR=1.623). The significance remained after 10,000 permutation tests to correct multiple testing (p=0.042). Re-selected age matched vertebral fracture case–control groups revealed similar associations in additive model (p=0.014, OR=1.927, 95%CI=1.142–3.253) and in dominant model (p=0.011, OR=2.231, 95%CI=1.200–4.148). However, no significant association was found between MATN3 polymorphisms and serum β-CTX, P1NP, 25(OH)D levels, or BMD. In linear regression, Haplotype-2 approached marginal significance in association with femoral neck BMD T-score (p=0.050), but this would account for only 0.2% of BMD variation in our sample. This study suggests that Haplotype-4 of MATN3 is associated with vertebral fracture risk independent of BMD in Chinese postmenopausal women. Efforts should be made to replicate our finding in other, similar and ethnically diverse, populations.Highlights: ► Four tagSNPs of MATN3 were determined in 1488 Chinese postmenopausal women. ► Haplotype-4 is associated with vertebral fracture risk independent of BMD. ► MATN3 polymorphisms are minor contributors to BMD variations. ► They may not contribute to variations of β-CTX, P1NP or 25(OH)D either.

Effects of neonatal castration and androgenization on sexual dimorphism in bone, leptin and corticosterone secretion - Corrected Proof

2012-01-27

Abstract: This study investigated the role of neonatal sex steroids in rats on sexual dimorphism in bone, as well as on leptin and corticosterone concentrations throughout the lifespan. Castration of males and androgenization of females were used as models to investigate the role of sex steroids shortly after birth. Newborn Wistar rats were divided into four groups, two male groups and two female groups. Male pups were cryoanesthetized and submitted to castration or sham-operation procedures within 24h after birth. Female pups received a subcutaneous dose of testosterone propionate (100μg) or vehicle. Rats were euthanized at 20, 40, or 120 postnatal days. Body weight was also measured at 20, 40, and 120days of age, and blood samples and femurs were collected. The length and thickness of the femurs were measured and the areal bone mineral density (areal BMD) was determined by dual-energy X-ray absorptiometry (DEXA). Biomechanical three-point bending testing was used to evaluate bone breaking strength, energy to fracture, and extrinsic stiffness. Blood samples were submitted to a biochemical assay to estimate calcium, phosphorus, alkaline phosphatase, leptin, and corticosterone levels. Weight gain, areal BMD and bone biomechanical properties increased rapidly with respect to age in all groups. In control animals, skeletal sexual dimorphism, leptin concentration, and dimorphic corticosterone concentration patterns were evident after puberty. However, androgen treatment induced changes in growth, areal BMD, and bone mass properties in neonatal animals. In addition, neonatally-castrated males had bone development and mechanical properties similar to those of control females. These results suggest that the exposure to neonatal androgens may represent at least one covariate that mediates dimorphic variation in leptin and corticosterone secretions. The study indicates that manipulation of the androgen environment during the critical period of sexual differentiation of the brain causes long-lasting changes in bone development, as well as serum leptin and corticosterone concentrations. In addition, this study provides useful models for the investigation of bone disorders induced by hypothalamic hypogonadism.Highlights: ► We showed the long-term organizational effects of neonatal androgen manipulation. ► Handling of the sex steroid milieu induced changes in bone and hormone secretion. ► This model provides an empirical tool for the study of skeletal sexual dimorphism. ► These data provide new insight into the dynamic complexity of bone mass homeostasis. ► The understanding of these mechanisms may allow for new therapies for bone health.

Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study - Corrected Proof

2012-01-27

Abstract: Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover.Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28.Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28.The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease.Highlights: ► Saracatinib significantly decreased bone resorption markers in advanced cancer. ► Suppression of Src kinase by saracatinib appears to inhibit osteoclast activity. ► Type I collagen degradation products significantly decreased with increasing dose. ► Anemia, nausea and anorexia were the most common AEs. ► Asthenia, constipation, fatigue and vomiting were also seen in ≥20% of patients.

Anatomical distribution of the degree of mineralization of bone tissue in human femoral neck: Impact on biomechanical properties - Corrected Proof

V. Sansalone, V. Bousson, S. Naili, C. Bergot, F. Peyrin, J.D. Laredo, G. Haïat — 2012-01-27

Abstract: Osteoporotic hip fractures represent a major public health problem associated with high human and economic costs. The anatomical variation of the tissue mineral density (TMD) and of the elastic constants in femoral neck cortical bone specimens is an important determinant of bone fragility. The purpose of this study was to show that a Synchrotron radiation microcomputed tomography system coupled with a multiscale biomechanical model allows the determination of the 3-D anatomical dependence of TMD and of the elastic constants (i.e. the mechanical properties of an anisotropic material) in human femoral neck.Bone specimens from the inferior femoral neck were obtained from 18 patients undergoing standard hemiarthroplasty. The specimens were imaged using 3-D synchrotron micro-computed tomography with a voxel size of 10.13μm, leading to the determination of the anatomical distributions of porosity and TMD. The elastic properties of bone tissue were computed using a multiscale model. The model uses the experimental data obtained at the scale of several micrometers to estimate the components of the elastic tensor of bone at the scale of the organ.Statistical analysis (ANOVA) revealed a significant effect of the radial position on porosity and TMD and a significant effect of axial position on TMD only. Porosity was found to increase in the radial direction moving from the periosteum inwards (p<10−5). At any given distance from the periosteum, porosity does not vary noticeably along the bone axis. TMD was found to be significantly higher (p<10−5) in the periosteal region than in other bone locations and decreases from the periosteal to the endosteal region with an average slope of 10.05g.cm−3.m−1, the decrease being faster in the porous part of the samples (average slope equal of 30.04g.cm−3.m−1) than in dense cortical bone. TMD was found to decrease from the distal to the proximal part of the femur neck (average slope of 6.5g.cm−3.m−1). Considering TMD variations in the radial direction induces weak changes of bone properties compared to constant TMD. TMD variations in the axial direction are responsible for a significant variation of elastic constants.These results demonstrate that the anatomical variations of TMD affect the bone elastic properties, which could be explained by the complex stress field in bone affecting bone remodeling. TMD spatial variations should be taken into account to properly describe the spatial heterogeneity of elastic coefficients of bone tissue at the organ scale.Highlights: ► We investigate the anatomical variation of DMB in human femoral neck using SR μCT. ► The stiffness coefficients are determined using a multiscale homogenization model. ► DMB is the highest in the periosteum and decreases in the endosteum. ► DMB decreases along the bone axis from the distal to the proximal part. ► The anatomical variations of DMB affect the elastic coefficients of bone tissue.

Medication adherence and fracture risk among patients on bisphosphonate therapy in a large United States health plan - Corrected Proof

2012-01-27

Abstract: The association between bisphosphonate adherence in the first 12months after therapy initiation and subsequent fracture risk was examined. Patients were identified from a large, commercially-insured population with integrated pharmacy and medical claims. Eligible patients were aged ≥45years, were new to osteoporosis therapy (no osteoporosis medication claims in prior year) with first (index) bisphosphonate claim between 1/1/2005 and 4/30/2008, and had continuous insurance coverage for ≥12months pre- and post-index. Patients with fracture claims≤12-months post-index were excluded. Adherence was assessed using the medication possession ratio (MPR) over 12-months post-index (i.e., sum of days' supply dispensed divided by 365days). Patients with a MPR>0.8 were considered adherent. The follow-up period to assess incident fracture began at month 13. The analysis included 33,558 new bisphosphonate users with mean age (SD) 59.5 (9.3) years; 94.0% were female. Median MPR at 12months was 0.61 for alendronate and risedronate; 0.58 for ibandronate. Proportionally more nonfracture patients (39.3%) had a MPR>0.8 compared with fracture patients (34.9%, p<0.001). In multivariate modeling of bisphosphonate users' experience, those with a MPR>0.8 had a 14% lower risk of subsequent fracture than those with MPR<0.5, after controlling for demographics, insurance type, select comorbidities, and other potential confounders (p=0.0459). In a large, commercially-insured population, suboptimal adherence with bisphosphonate treatment was associated with increased fracture risk even after controlling for potential confounders.Highlights: ► We examined bisphosphonate (BP) adherence in first year and subsequent fracture risk. ► Median medication possession ratio (MPR) and interquartile range were 0.61 and 0.69. ► BP users with MPR >0.8 had significantly lower fracture risk than nonadherent users.

The effect of high versus low loading on bone strength in middle life - Corrected Proof

2012-01-27

Abstract: While bone mass and geometry are largely genetically determined, mechanical loading is considered to be an important additional determinant. This study investigates to what extent very high mechanical loading begun at a young age and sustained afterward can affect tibia bone mass and geometry in middle age. Cohorts from a common ethnic background, with a history of very high and very low tibia bone loading based on an assessment of their activities according their strain levels were compared. The study hypothesis was that the tibia bone density and geometric strength parameters would be greater in the high bone loading cohort.Subjects from a group of elite infantry recruits who sustained a 31% incidence of stress fractures during their basic training in 1983, were reviewed 25years later. The tibia bone strength of 25 of these soldiers, 11 of whom had sustained stress fractures, was compared to a group of 20 subjects who received exemption from military service in 1982–5 because they were religious scholars and who continued these studies afterwards. Anthropometric measurements were made. The bone density and geometric strength of the tibia was assessed by quantitative computerized tomography (QCT). The average daily dietary intake and metabolic expenditure of subjects were assessed by questionnaires.At the 25year follow-up soldiers were on an average 3cm taller than the religious scholars (p=0.02) and had lower abdominal girths (p=0.03). There was no difference in the tibia cortical density between cohorts in spite of the fact that the religious scholars had lower daily calcium intakes (p=0.02). Soldiers had stronger tibias based on geometric engineering criteria. The mean area moments of inertia (p=0.02, p=0.04) and polar moments of inertia (p=0.02) were 16% larger in the soldier cohort. By multivariate regression analysis greater height, weight and daily energy expenditure were related to larger bone geometric strength parameters. According to semipartial eta-square analysis, between 39% to 45% of the variance in the area moments of inertia between the cohorts was attributable to these three parameters. The religious scholars burned less calories daily, principally because they did no sport activity (p=0.001). There was no difference in tibia bone strength parameters between soldiers who did and did not sustain stress fractures in their 1983 basic training.In conclusion, in a middle age population with a common ethnic origin, the high bone loading cohort had stronger tibias than the low bone loading cohort based on larger geometric strength properties and not because of higher cortical density. In spite of being at the extremes of the bone loading spectra, the tibia area moment of inertia of the two cohorts in this study differed by only 16%, with part of this difference attributable to factors other than bone loading. We do not know for sure if the difference in the geometric properties is related to high bone loading or whether people with stronger bones are more likely to engage in high bone loading. Healthy male subjects who sustained stress fractures at a young age do not have weaker tibias at middle age according to QCT measurements.Highlights: ► High bone loading beginning at an early age seems to strengthen the tibia by increasing geometric strength properties. ► The area moment of inertia between extremely high and low loading groups differed by 16 per cent, but some of this difference was related to other factors. ► High bone loading beginning at an early age did not increase the tibia cortical bone density. ► Healthy male subjects who sustained stress fractures at a young age did not have weaker tibias at middle age.

Micro and macroarchitectural changes at the tibia after botulinum toxin injection in the growing rat - Corrected Proof

B. Bouvard, G. Mabilleau, E. Legrand, M. Audran, D. Chappard — 2012-01-25

Abstract: The aim of this study was to analyze bone microarchitecture and macroarchitecture of tibia in a disuse model in growing rats. Eight-weeks-old Copenhagen rats were injected intramuscularly with 1.5 units BTX in the quadriceps muscle of the right hind limb. Saline injection was done at the left hind limb to serve as control. Five rats were killed at day 1 and represented the baseline group (D1), 5 rats were killed at day 14 (D14), 5 at day 21 (D21), 5 at day 28 (D28) and 5 at day 35 (35). For each group, muscle surface, parameters of bone microarchitecture and macroarchitecture (including length, width and curvature of the tibia) were measured using microtomography. Paralysis occurred as soon as day 2. At the left hind limb, muscle surface area, cortical thickness, cross sectional total area and growth in length significantly increased during the time study. At the right hind limb, muscle surface area, bone trabecular volume, and cortical thickness decreased as soon as day 14 associated with an increased cortical porosity. Growth in length did not differ from left side; cross sectional total area did not increase and the diaphyseal cross section acquired a more rounded shape. There was no modification of the curvature between right and left hind limbs during the time study. In this murine model of unilateral muscle paralysis in growing animals, we showed a rapid muscle loss leading to a decreased growth in width; however growth in length and curvature were unaltered.Highlights: ► A single Botulinum toxin injection was done in the quadriceps of growing rats. ► It induced disuse associated with muscle atrophy and bone loss. ► Micro and macroarchitectural changes were analyzed by microCT with new algorithms. ► Disuse did not interfere with bone growth nor bone curvature. ► Macroarchitectural changes consisted of more round bones on transverse sections.

Vertebral fracture assessment in asymptomatic men and its impact on management - Corrected Proof

A. El Maghraoui, A. Mounach, A. Rezqi, L. Achemlal, A. Bezza, I. Ghozlani — 2012-01-24

Abstract: Introduction: Recognition of vertebral fractures (VFs) change the patient's diagnostic classification, estimation of fracture risk, and threshold for pharmacological intervention. Vertebral fracture assessment (VFA) enables the detection of VFs in the same session as bone mineral density (BMD) testing.Objective: To study prevalence and risk factors of VFs using VFA in asymptomatic men and measure its impact on patients' management.Methods: We enrolled791 men aged between 45 and 89 (mean age, weight and BMI of 62.4±8.6) (45 to 89) years, 74.9±12.7 (40 to 163) and 26.3±4.0 (16.6 to 43.8) kg/m2, respectively. Lateral VFA images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative (SQ) approach and morphometry.Results: VFs were identified in 318 (40.3%): 206 (26.0%) had grade 1 and 112 (14.2%) had grade 2 or 3. As would be expected, the prevalence of VFA-detected fractures globally increased significantly with age and as BMI and BMD declined. A fracture was identified on VFA in 85 (32.4%) of men with normal BMD (6.9% had grade 2/3 VFs) and in 144 (35.8%) with osteopenia (11.7% had grade 2/3 VFs). Stepwise regression analysis showed that presence of VFs was independently related to the osteoporotic status (OR=4.761, 95%CI [2.956–7.668]; p<0.0001) and current smoking (OR=1.717, 95%CI [1.268–2.323]; p=0.002).Conclusion: Our results support the recommendation to enlarge the indications of VFA to all the men referred for DXA measurement.Highlights: ► VFs recognition change the fracture risk estimation and threshold for treatment. ► Using VFA in 791 men, we found VFs in 40% (13% had moderate/severe VFs). ► VFA should be indicated to all the men needing DXA measurement.

Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints - Corrected Proof

2012-01-13

Abstract: Osteoarthritis (OA) is a degenerative joint disease and one of the leading causes of disability in the United States and across the world. As a disease of the whole joint, OA exhibits a complicated etiology with risk factors including, but not limited to, ageing, altered joint loading, and injury. Subchondral bone is hypothesized to be involved in OA development. However, direct evidence supporting this is lacking. We previously detected measurable transport of solute across the mineralized calcified cartilage in normal joints, suggesting a potential cross-talk between subchondral bone and cartilage. Whether this cross-talk exists in OA has not been established yet. Using two models that induced OA by either ageing or surgery (destabilization of medial meniscus, DMM), we tested the hypothesis that increased cross-talk occurs in OA. We quantified the diffusivity of sodium fluorescein (mol. wt. 376Da), a marker of small-sized signaling molecules, within calcified joint matrix using our newly developed fluorescence loss induced by photobleaching (FLIP) method. Tracer diffusivity was found to be 0.30±0.17 and 0.33±0.20μm2/s within the calcified cartilage and 0.12±0.04 and 0.07±0.03μm2/s across the osteochondral interface in the aged (20–24-month-old, n=4) and DMM OA joints (5-month-old, n=5), respectively, which were comparable to the control values for the contralateral non-operated joints in the DMM mice (0.48±0.13 and 0.12±0.06μm2/s). Although we did not detect significant changes in tissue matrix permeability in OA joints, we found i) an increased number of vessels invading the calcified cartilage (and sometimes approaching the tidemark) in the aged (+100%) and DMM (+50%) joints relative to the normal age controls; and ii) a 60% thinning of the subchondral bone and calcified cartilage layers in the aged joints (with no significant changes detected in the DMM joints). These results suggested that the capacity for cross-talk between subchondral bone and articular cartilage could be elevated in OA. Further studies are needed to identify the direction of the cross-talk, the signaling molecules involved, and to test whether subchondral bone initiates OA development and could serve as a pharmaceutical target for OA treatment.This article is part of a Special Issue entitled “Osteoarthritis”.Highlights: ► Bone-cartilage cross-talk examined in two models (surgical DMM and ageing) of OA. ► Decreased (but not significant) tissue permeability in mineralized ECM of OA joints. ► Increased vessels invasion in aged (+100%) and DMM (+50%) joints vs. controls. ► 60% thinning of thickness in aged joints and no changes in DMM joints vs. controls. ► Bone-cartilage cross-talk elevated in the two OA models via different mechanisms.

Genetic factors in OA pathogenesis - Corrected Proof

Kay Chapman, Ana M. Valdes — 2012-01-04

Abstract: Osteoarthritis (OA) is known to have an important genetic component and human genetic studies can help unravel the molecular mechanisms responsible for joint damage and nociception involved in OA. Genetic studies in humans have identified molecules involved in signaling cascades that are important for the pathology of the joint components such as the bone morphogenetic protein growth differentiation factor 5 (GDF5). Genomewide association scans (GWAS) in Asians have uncovered a likely role for structural extracellular matrix components (DVWA), and for molecules involved in immune response (HLA class II DQB1 and BTNL2) but these genes are not associated in Caucasian patients. In Caucasians a ~300 kilobase region in chromosome 7q22 containing several genes has been found to be reproducibly associated with OA. A recent European GWAS taking advantage of imputation techniques has uncovered a variant in the MCF2L gene as significantly associated with large joint OA. MCF2L is involved in neurotrophin mediated regulation of cell motility in the peripheral nervous system, and thus potentially implicated in nociception in OA. As the number of OA cases with genomewide genotyping increases it is expected that many more reproducible variants implicated in OA will be reported.This article is part of a Special Issue entitled Osteoarthritis.Highlights: ► We review the genetic associations reported to date with knee and hip osteoarthritis. ► Different genetic associations are seen in Asian populations from those of European descent. ► In European-descent populations three genetic variants have been reported to be associated with genome-wide significance with OA. ► These variants map to the GDF5 and MCF2L genes, and the COG5/GRP22 cluster (function as yet unknown). ► GDF5 is a chondroprotective growth factor. MCF2L is involved in neurotrophin regulated cell motility and potentially in nociception.

Diagnosis of osteoarthritis: Imaging - Corrected Proof

Hillary J. Braun, Garry E. Gold — 2011-12-30

Abstract: Osteoarthritis (OA) is a chronic, debilitating joint disease characterized by degenerative changes to the bones, cartilage, menisci, ligaments, and synovial tissue. Imaging modalities such as radiography, magnetic resonance imaging (MRI), optical coherence tomography (OCT), and ultrasound (US) permit visualization of these structures and can evaluate disease onset and progression. Radiography is primarily useful for the assessment of bony structures, while OCT is used for evaluation of articular cartilage and US for ligaments and the synovium. MRI permits visualization of all intraarticular structures and pathologies, though US or OCT may be preferential in some circumstances. As OA is a disease of the whole joint, a combination of imaging techniques may be necessary in order to gain the most comprehensive picture of the disease state.This article is part of a Special Issue entitled Osteoarthritis.

Serum xylosyltransferase 1 level increases during early posttraumatic osteoarthritis in mice with high bone forming potential - Corrected Proof

2011-12-19

Abstract: Increased proteoglycan (PG) synthesis is essential for the stimulation of cartilage repair processes that take place during the reversible phase of osteoarthritis (OA). In articular cartilage, xylosyltransferase 1 (Xylt1) is the key enzyme that initiates glycosaminoglycan (GAG) chain synthesis by transferring the first sugar residue to the PG core protein. Biological activity of PGs is closely linked to GAG biosynthesis since their polyanionic nature directly contributes to the proper hydration and elastic properties of the cartilage tissue present at the articular interface. The aim of this study was to investigate whether variations in the level of Xylt1 present in serum can be used to predict OA disease progression. The influence of bone forming activity on the systemic release of this enzyme was addressed by experimentally-inducing OA in mice of two different genetic backgrounds that were previously characterized for their distinct bone metabolism: C57BL/6J (B6, high bone remodelers) or C3H/HeJ (C3H, high bone formers). Serum was collected after medial meniscectomy or sham surgeries in young adult mice of these two strains over a period of 3.5months at which point knee histopathology was assessed. A significant increase in serum Xylt1 levels observed shortly after meniscectomy positively correlated with severe cartilage damage evaluated by histological assessment at later time points in mice of the C3H background. In contrast, no temporal regulation of Xylt1 level was found between meniscectomies and control surgeries in B6 mice, which developed OA at a slower rate. Additionally, longitudinal evaluation of the serum levels of other markers of cartilage/bone metabolism (C1,2C, osteocalcin) did not reveal any association with late knee damages. Our results strongly support the idea that serum Xylt1 has a clinical value for monitoring risk of OA progression in young adults with high bone forming potential. Ultimately, the understanding of posttraumatic mechanisms regulating PG synthesis and their modification by GAG will be essential so that interventions that stimulate cartilage regrowth can be undertaken prior to irreversible destruction of the joint tissue. This article is part of a Special Issue entitled .Highlights: ► Serum level of xylosyltransferases is an indicator of proteoglycan synthesis rate. ► Serum Xylt1 level transiently increases following meniscectomy only in C3H/HeJ mice. ► Meniscectomy induces faster OA progression in C3H/HeJ mice than in C57BL/6J mice. ► Early increase in serum Xylt1 correlates with later cartilage damage in C3H/HeJ. ► Serum levels of Xylt1 may be used as a biomarker to predict OA.

Osteochondral alterations in osteoarthritis - Corrected Proof

Sunita Suri, David A. Walsh — 2011-11-18

Abstract: Osteoarthritis (OA) is a major cause of pain and disability in the aging population, but its pathogenesis remains incompletely understood. Alterations beneath the articular cartilage at the osteochondral junction are attracting interest as possible mediators of pain and structural progression in OA. Osteochondral changes occur early during the development of OA and may aggravate pathology elsewhere in the joint. Loss of osteochondral integrity removes the barrier between intra-articular and subchondral compartments, exposing subchondral bone and its nerves to abnormal chemical and biomechanical influence. Osteochondral plasticity results in a merging of tissue compartments across the junction. Loss of the clearly differentiated demarcation between bone and articular cartilage is associated with invasion of articular cartilage by blood vessels and sensory nerves, and advancing endochondral ossification. Increased subchondral bone turnover is intimately associated with these alterations at the osteochondral junction. Cells signal across the osteochondral junction, and this cross-talk may be both a consequence of, and contribute to these pathological changes. Bone turnover, angiogenesis and nerve growth are also features of other diseases such as osteoporosis and cancers, for which therapeutic interventions are already advanced in their development. Here we review pathological changes at the osteochondral junction and explore their potential therapeutic implications for OA. This article is part of a Special Issue entitled .

Tissue engineering approaches for osteoarthritis - Corrected Proof

Frank P. Luyten, Johan Vanlauwe — 2011-11-14

Abstract: With the ageing of the population and the major advances in targeted drug treatments, there is in medicine a shift in attention from survival towards quality of life. Therefore new challenges are emerging in modern health care. Preventive and personalized medicine have been identified as key steps in this context. New targeted biologicals for musculoskeletal diseases such as chronic arthritis have entered daily clinical practice, thereby not only controlling symptoms and signs, inflammation and destruction, but also maintaining function of the joints. The last aspect is essential for the independence of the individual and critical for the quality of life. Since the lifespan of prosthetic devices will always remain limited, new treatment approaches to repair skeletal structures need to be devised for the young and middle aged individuals with skeletal and joint damage caused by either congenital, traumatic, or inflammatory conditions. It is believed that regenerative medicine and more specifically tissue engineering may fill this void to some extent. Indeed, recent cellular therapeutics and combination products, now resorting under a new regulatory class of Advanced Medicinal Therapeutic Products, provide indications that progress is being made with clinically relevant outcomes in well-defined patient populations. For osteoarthritis, a joint disease leading to joint decompensation, novel tissue engineering therapies are being explored and, although most of the developments are still in early phase clinical studies, there are sufficient positive signals to pursue these novel therapeutic approaches in clinics. This article is part of a Special Issue entitled “Osteoarthritis”.

Future therapeutics for osteoarthritis - Corrected Proof

Johanne Martel-Pelletier, Lukas M. Wildi, Jean-Pierre Pelletier — 2011-11-14

Abstract: Osteoarthritis (OA) is a disease of the joints that affects several million individuals worldwide. This disease, which involves mainly the diarthrodial joints, is chronic and develops slowly over decades, making it very difficult to precisely identify the different etiological and risk factors that influence its onset. At present, most therapies for OA are symptomatic. This review will focus on new OA therapeutics in development that are directed toward pain relief as well as others with the potential to reduce or stop the progression of the disease (DMOADs).This article is part of a Special Issue entitled “Osteoarthritis”.

50 Withdrawn - Corrected Proof

2006-02-17