With aging there is an increase in fracture risk, due largely to a progressive decline in bone mass and strength (osteoporosis). An estimated 2 million osteoporotic fractures occur annually in the U.S. at a cost of $17 billion. The predominant treatment for osteoporosis is the use of drugs that block bone resorption (anti-resorptive or anti-catabolic). Yet, a main feature of skeletal aging is a decline in the rate of bone formation, and there exists an unmet clinical need for anabolic strategies to offset this decline. When mechanical forces are applied to bones cyclically (i.e., load-unload, load-unload, etc.) they can stimulate an increase in bone formation that leads to accrual of bone mass. Thus, mechanical loading of the skeleton represents a powerful anabolic strategy with potential to treat osteoporosis. However, it is unclear if the aging skeleton loses its ability to respond to loading. The long-term goal of this project it to determine how age influences the biological response of bones to mechanical loading, i.e., mechanoresponsiveness. Results from the past funding period indicate that aged mice responded to loading as well as younger mice, which leads to the overall hypothesis - age does not limit the ability of mechanical loading to stimulate increased bone formation. In order for bones from aged animals to increase bone formation, they must overcome a low baseline rate of bone formation and a lack of committed osteoblasts. Thus, loading must first recruit osteoblasts at the site of bone formation by differentiation of uncommitted lining cells or osteoprogenitors, a process that may also involve cell proliferation. One mechanism by which bone formation may be stimulated at all ages is through Wnt/Lrp signaling. Using the tibial compression loading model, we propose to determine the relative importance of osteoblast recruitment and the requirement for Wnt/Lrp signaling in the mechanoresponse of bones from mice across their life spans.
Aim 1 A: Apply in vivo mechanical loading to mice at multiple ages, and examine responses to loading at the tissue level (microCT, dynamic histomorphometry) and the molecular level (qPCR gene expression).
Aim 1 B: Using an osteoblast reporter mouse, determine the effect of mechanical loading on local osteoblast recruitment as a function of age.
Aim 1 C: Using mice in which replicating osteoblast progenitors are conditionally ablated, determine the importance of cell proliferation on loading-induced bone formation as a function of age.
Aim 2 A: Using a Wnt reporter mouse, evaluate the relationship between mechanical strain magnitude and activation of canonical Wnt signaling in bones from young and old mice.
Aim 2 B: Determine if interruption of anabolic Wnt/Lrp signaling in osteoblasts precludes the anabolic response of bones to mechanical loading in young and old mice. Our findings will contribute to the field of skeletal biology in two important ways: 1) they will either support or refute the potential of loading to increase bone mass in the aged skeleton, and 2) they will identify age-related differences (and similarities) in cellular and molecular responses to loading.

Public Health Relevance

With aging there is an increase in fracture risk, due largely to a progressive decline in bone mass (osteoporosis). We will examine the potential of mechanical loading (i.e., the repetitive application of physical forces) to increase bone mass in young and old animals. If we show that mechanical stimulation can increase bone mass in old animals, it will motivate the future development of physical intervention strategies (e.g., exercise) to enhance bone mass and reduce fracture risk in elderly women and men.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Sharrock, William J
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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
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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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