There is an unmet clinical need for anabolic strategies to treat the 50 million women and men in the U.S. with severely or moderately low bone mass (osteoporosis or osteopenia, respectively). Mechanical loading is a potent, physiological means to stimulate bone formation and increase bone mass. However, with aging, humans and rodents have a decline in their ability to form bone in response to exercise and other forms of mechanical loading. The basis for this decline remains unknown. Our long-term goal is to identify key mechanisms in loading-induced bone formation in the adult skeleton so that we may inform future strategies to increase bone mass in osteoporosis. Our focus in this project is on the origin of osteoblasts that form bone in response to mechanical loading, and on the Wnt signaling pathway. We propose experiments using a physiological model of bone anabolism ? murine axial tibial compression ? that will extend our scientific knowledge as follows. First, we will determine the origin of osteoblasts (in young-adult and old mice) that form bone in response to in vivo mechanical loading. Modern lineage tracing and histological methods will be applied to address this basic unknown. Second, we will determine if osteoblast lineage cells in old mice are less proliferative than in young mice in response to in vivo loading. If so, this will provide motivation to develop strategies to target this deficit to enhance mechanoresponsiveness. Third, motivated by the finding that Wnts1 and 7b are highly responsive to bone mechanical loading, we will determine the role of these ligands produced by osteoblasts in loading-induced bone formation. Inducible, conditional deletion of Wnt 1 and 7b will be accomplished in adult mice, followed by mechanical loading and assessment of bone formation, cell proliferation and gene expression. If loss of Wnt 1 or 7b mimics the effects of aging, it will motivate targeted treatment strategies to rescue the mechanoresponsiveness of the aged skeleton. In summary, the decline in the anabolic response of bone to mechanical loading is a central feature of skeletal aging. The proposed studies will clarify the basis for this decline while addressing fundamental mechanisms that support loading-induced bone formation.

Public Health Relevance

In the U.S., 50 million women and men have moderately or severely low bone mass (osteopenia or osteoporosis, respectively) which increases their risk for fracture. Physical loading of the skeleton and weight-bearing exercise can increase bone mass, but is less effective in older people and animals for reasons that are not known. This project will address this issue by examining the biological responses of bones in young and old mice to physical loading.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Nicks, Kristy
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Washington University
Schools of Medicine
Saint Louis
United States
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Sun, David; Brodt, Michael D; Zannit, Heather M et al. (2018) Evaluation of loading parameters for murine axial tibial loading: Stimulating cortical bone formation while reducing loading duration. J Orthop Res 36:682-691
Holguin, Nilsson; Silva, Matthew J (2018) In-Vivo Nucleus Pulposus-Specific Regulation of Adult Murine Intervertebral Disc Degeneration via Wnt/Beta-Catenin Signaling. Sci Rep 8:11191
Holguin, Nilsson; Brodt, Michael D; Silva, Matthew J (2016) Activation of Wnt Signaling by Mechanical Loading Is Impaired in the Bone of Old Mice. J Bone Miner Res 31:2215-2226
Jepsen, Karl J; Silva, Matthew J; Vashishth, Deepak et al. (2015) Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res 30:951-66
Amend, Sarah R; Uluckan, Ozge; Hurchla, Michelle et al. (2015) Thrombospondin-1 regulates bone homeostasis through effects on bone matrix integrity and nitric oxide signaling in osteoclasts. J Bone Miner Res 30:106-15
Chen, Jianquan; Holguin, Nilsson; Shi, Yu et al. (2015) mTORC2 signaling promotes skeletal growth and bone formation in mice. J Bone Miner Res 30:369-78
Holguin, Nilsson; Aguilar, Rhiannon; Harland, Robin A et al. (2014) The aging mouse partially models the aging human spine: lumbar and coccygeal disc height, composition, mechanical properties, and Wnt signaling in young and old mice. J Appl Physiol (1985) 116:1551-60
Holguin, Nilsson; Brodt, Michael D; Sanchez, Michelle E et al. (2014) Aging diminishes lamellar and woven bone formation induced by tibial compression in adult C57BL/6. Bone 65:83-91
Wu, P; Holguin, N; Silva, M J et al. (2014) Early response of mouse joint tissue to noninvasive knee injury suggests treatment targets. Arthritis Rheumatol 66:1256-65
Patel, Tarpit K; Brodt, Michael D; Silva, Matthew J (2014) Experimental and finite element analysis of strains induced by axial tibial compression in young-adult and old female C57Bl/6 mice. J Biomech 47:451-7

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