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R-spondin 1 promotes vibration-induced bone formation in mouse models of osteoporosis

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Abstract

Bone tissue adapts to its functional environment by optimizing its morphology for mechanical demand. Among the mechanosensitive cells that recognize and respond to forces in the skeleton are osteocytes, osteoblasts, and mesenchymal progenitor cells (MPCs). Therefore, the ability to use mechanical signals to improve bone health through exercise and devices that deliver mechanical signals is an attractive approach to age-related bone loss; however, the extracellular or circulating mediators of such signals are largely unknown. Using SDS-PAGE separation of proteins secreted by MPCs in response to low-magnitude mechanical signals and in-gel trypsin digestion followed by HPLC and mass spectroscopy, we identified secreted proteins up-regulated by vibratory stimulation. We exploited a cell senescence-associated secretory phenotype screen and reasoned that a subset of vibration-induced proteins with diminished secretion by senescent MPCs will have the capacity to promote bone formation in vivo. We identified one such vibration-induced bone-enhancing (vibe) gene as R-spondin 1, a Wnt pathway modulator, and demonstrated that it has the capacity to promote bone formation in three mouse models of age-related bone loss. By virtue of their secretory status, some vibe proteins may be candidates for pre-clinical development as anabolic agents for the treatment of osteoporosis.

Key message

  • Mesenchymal stem cells respond to low magnitude mechanical signals (vibration).

  • R-Spondin 1 is upregulated by mechanical signals and secreted.

  • R-Spondin 1 promotes bone formation in three mouse models of osteoporosis.

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Acknowledgments

This work was supported by National Institutes of Health/ National Institute on Aging grants R01AG028873 (R.J.P) and P01AG031862 (D.C.S., F.B.J.). The Juvent 1000 Dynamic Motion Platform was a generous gift from Mary Leonard, MD, MSCE (Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania).

Disclosure statement

The authors declare no conflicts of interest related to the work presented in this paper.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Haitao Wang, Craig Israelite & Robert J. Pignolo

  2. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Tracy A. Brennan, Elizabeth Russell, Jung-Hoon Kim, Kevin P. Egan & Robert J. Pignolo

  3. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Qijun Chen & Frederick B. Johnson

  4. The Wistar Institute, Philadelphia, PA, 19104, USA

    David C. Schultz

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  1. Haitao Wang
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Correspondence to Robert J. Pignolo.

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Wang, H., Brennan, T.A., Russell, E. et al. R-spondin 1 promotes vibration-induced bone formation in mouse models of osteoporosis. J Mol Med 91, 1421–1429 (2013). https://doi.org/10.1007/s00109-013-1068-3

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  • DOI: https://doi.org/10.1007/s00109-013-1068-3

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