Bone is a dynamic organ that is known to adjust in mass, material and architectural properties with respect to the load environment. The progressive decline in muscle mass, sti-ength/performance (sarcopenia) and bone loss (osteopenia/osteoporosis) that occurs with aging suggeste a functional coupling between the diseases. As the osteocyte is thought to be the mechanosensory cell in bone, an age-related reduction in ite ability to respond to load would have significant consequences on bone mass. We have shown that the Wnt/|3-catenin signaling pathway is a critical component of bone responsiveness to mechanical loading and is rapidly activated in osteocytes following the in vivo application of load. Recent data shows that loss of one allele of P-catenin in osteocytes prevents new bone formation in response to mechanical loading. Furthermore, we have provocative preliminary data that muscle derived soluble factor(s) enhance the effecte of loading on the Wnt/p-catenin pathway in osteocytes (see Subproject 1), but that muscle converte from producing bone beneficial factors to producing bone detrimental factors with aging. This project will test the hypothesis that aging alters the osteocyte's ability to respond to mechanical loading. To test this hypotiiesis we propose three specific aims.
In Aim 1 we wiil determine the effect of aging on the ability of the osteocyte to respond to mechanical loading.
In Aim 2 we will determine the effect of aging on ttie osteocyte sti^in environment.
In Aim 3 we will detennine in if muscle inactivation has an affect on the anabolic response of bone and whether this is latered with age.
These aims will be accomplished using young (5 mo old), mature (12 mo) and aged (22 mo) mouse models of nonmal and a new Cre mouse we have generated that allows us to temporally and specifically delete genes in osteocytes. In vitro studies using bone and muscle cell model systems and primary cells will be used to dissect the molecular basis for the changes we observe in vivo. Overall these aims will enable us to determine the magnitude of strain necessary to initiate the biological response of Wnt/p-catenin activation, whether aging alters the intrinsic ability of the osteocyte to respond to load and if the osteocyte regulates ite strain environment through p-catenin expression.

Public Health Relevance

The studies proposed in this project are paradigm setting and have the potential to launch a new direction for the study of musculoskeletal diseases and how aging alters these nonnal processes. Knowledge from these studies on how the osteocyte responds to mechanical load and how this response is conditioned by muscle derived factors will produce new targets for drug development to treat sarcopenia and osteoporosis. PROJECT/PERFORMANCE SrTE(

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-9 (J2))
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University of Missouri Kansas City
Kansas City
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Thiagarajan, Ganesh; Lu, Yunkai; Dallas, Mark et al. (2014) Experimental and finite element analysis of dynamic loading of the mouse forearm. J Orthop Res 32:1580-8
Huang, Jian; Hsu, Yi-Hsiang; Mo, Chenglin et al. (2014) METTL21C is a potential pleiotropic gene for osteoporosis and sarcopenia acting through the modulation of the NF-?B signaling pathway. J Bone Miner Res 29:1531-40
Javaheri, Behzad; Stern, Amber Rath; Lara, Nuria et al. (2014) Deletion of a single *-catenin allele in osteocytes abolishes the bone anabolic response to loading. J Bone Miner Res 29:705-15
Pan, Zui; Brotto, Marco; Ma, Jianjie (2014) Store-operated Ca2+ entry in muscle physiology and diseases. BMB Rep 47:69-79
Dallas, Sarah L; Prideaux, Matthew; Bonewald, Lynda F (2013) The Osteocyte: An Endocrine Cell and More. Endocr Rev :