Original Full Length ArticleLow magnitude mechanical signals mitigate osteopenia without compromising longevity in an aged murine model of spontaneous granulosa cell ovarian cancer☆,☆☆
Highlights
► Low intensity vibration (LIV) effects on bone were examined in mice prone to granulosa cell tumorigenesis. ► Exposure to LIV did not compromise longevity following 1 year of daily treatment. ► Bone preservation was evident in tibiae and vertebrae of LIV mice as compared to controls. ► MSCs were significantly lower in the bone marrow of LIV-treated animals and in those lacking pathology. ► Overall tumor incidence was lower in LIV mice, and involved fewer organs when disease was evident.
Introduction
Cancer progression is often complicated by rapid declines in bone density. This osteopenia is exacerbated by the catabolic pressures of radioablative or chemotherapeutic interventions, placing the individual at an elevated risk of fracture [1]. Just as exercise is considered an effective means of reducing the risk of cancer [2], sedentary individuals are at an increased risk of developing tumors at a wide range of anatomic sites [3]. Both cancer and its treatment regimens disrupt adult stem cell reservoirs residing in the bone marrow, populations essential to maintaining and regenerating injured tissues and organs, further suppressing the ability to repair damaged connective tissue [4].
Taking advantage of the skeletal system's inherent sensitivity to mechanical stimuli [5], recent evidence indicates that low-magnitude, high-frequency mechanical signals induced via low intensity vibration (LIV) are anabolic to bone, perhaps serving as an exercise surrogate by introducing the spectral content of muscle contractibility into the skeletal system [6], [7], [8], [9], [10], [11]. To some degree, the osteogenic nature of these mechanical signals is realized by biasing bone marrow-derived MSCs towards osteoblastogenesis, while suppressing the formation of adipose tissue [12], [13]. Conversely, sedentary individuals, the infirm, or those subject to disuse due to injury, shift the fate of the bone marrow progenitor pool towards adipogenesis [6], [7], [13], undermining the pool of cells that contribute to skeletal mass and regeneration [14], [15], [16]. These preclinical and clinical data indicate that the absence of mechanical signals potentiates a “default” pathway of fat formation, while physical stimuli, such as exercise, can encourage lineage commitment to higher order connective tissues, including bone, muscle, ligament, and tendon.
The capacity of exercise in general, and LIV in particular, to be anabolic to bone suggests that mechanical signals may be a suitable means of protecting the skeletal system from the catabolic consequences of cancer and its therapies. However, considering the capacity of LIV to influence stem cell activity in the bone marrow [13], [17], [18], it is also reasonable to raise concern that these mechanical signals may enable the formation of a stromal framework of solid tumors [19], [20], [21], [22], thus facilitating progression of the disease. This concern is magnified at the molecular level, where β-catenin, through its cytoplasmic association with the intracellular domain of E-cadherin, serves to partially mediate Wnt/Catenin osteoblastogenic signaling in response to mechanical signals [8], yet as an oncogene it is implicated in a wide array of human cancers [23]. Further, the MSC itself is suggested to be a key component of the tumor microenvironment, with evidence for a role in both suppressing [24], and promoting [25] tumor growth. Recent work which considered MSC harvested from human epithelial ovarian microenvironments showed, in comparison to non-pathological MSCs, that cancer-MSC were able to enhance ovarian tumorigenesis [26]. This suggests that mechanical regulation of MSC commitment could have far-reaching effects on cancer growth, both by driving MSC towards the formation of bone, and/or influencing the progression of the tumor itself.
The experiments reported herein use a mouse model genetically prone to tumorigenesis to determine if the introduction of LIV compromises longevity, protects bone density, promotes tumor formation, and/or biases the fate of bone marrow-derived progenitor populations. The uniqueness of this mouse strain resides in the development of spontaneous granulosa cell tumors (GCT) of the ovary within ~ 30% of the population [27], [28]. Tumorigenic onset occurs at approximately 3 months of age, which then proceed to metastasize to the lungs and liver [27], [28], [29].
Section snippets
Animal model
All experiments and procedures were reviewed and approved by the Stony Brook University Institutional Animal Care and Use Committee (IACUC). An F1 strain of 70 female, SWRxSWXJ-9 mice (The Jackson Laboratory; Bar Harbor, ME), crossbred to create a gct1 mutation, was chosen for its genetic propensity to develop spontaneous granulosa cell tumors at around 3 months of age. Tumorigenesis occurs naturally and spontaneously in these animals, meaning that no external pressures, such as those
Longevity
Over the course of the study, 8 animals were lost within the LIV group (27%), while 10 were lost in AC (33%), indicating similar survivability over the 1 year course of the study (Fig. 1; p = 0.62). Unless otherwise noted, data from animals that died over the course of the study were not included in the analysis.
Bone morphology
Micro-CT analyses of the proximal tibia indicated that trabecular bone volume (Tb.BV) and bone volume fraction (Tb.BV/TV) in the 64w old AC had decreased by − 47% (p < 0.01) and − 45% (p <
Discussion
Osteoporosis, a common co-morbidity of cancer [37], is often exacerbated by aggressive chemo- and radio-therapies [37], [38], [39], [40], [41]. Cancer-associated declines in bone strength ultimately increase the risk of fracture, while disease or treatment-based disruption of the bone marrow stem cell pool could compromise the tissue repair process [42]. While antiresorptive agents (e.g., bisphosphonates) have helped cancer patients to mitigate these losses [43], [44], [45], concerns arise
Conclusion
In summary, using a mouse model of spontaneous granulosa cell ovarian cancer, low magnitude mechanical signals, induced non-invasively using low intensity vibration, mitigated the long-term loss of bone relative to age-matched controls. This skeletal endpoint was achieved without compromising survival. Further, the decreased tumor burden, considered in concert with significantly lower mesenchymal stem cell populations measured in the bone marrow of LIV mice, suggest both the skeletal and
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Funding: This work was supported by National Institute of Health grant AR 43498 and the Center for Biotechnology, Stony Brook University.
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Conflict of interest: C. T. Rubin is a founder of Marodyne Medical, Inc. and has a USPTO application under review for the ability of mechanical signals to control metabolic disorders. The other authors declare no competing interests.