Osteoporosis and Sarcopenia are diseases of bone and muscle loss that represent a major clinical problem in the aged population. These conditions often occur together, suggesting common pathogenic mechanisms and/or crosstalk between muscle and bone. Cunent treatmente for osteoporosis target osteoclast or osteoblast activity to maintain bone mass, but tiie osteocyte has been overiooked. Exciting recent research has shown that osteocytes are major regulators of osteoblast and osteoclast function and that regulation of the Wnt/3-catenin pathway by osteocytes may play a central role inregulationof bone mass. Our laboratory has taken a unique approach to examining osteoblast-osteocyte interactions using fiuorescence live imaging approaches in bone cell and organ culture models. We have shown that osteoblasts on the bone surface are motile cells and that assembly of ECM proteins In living osteoblasts is a highly dynamic process that is integrated with cell motility. We have also shown that Sclerostin and Wnts, both produced by osteocytes, can alter osteoblast motility and differentiated function. Building on these observations, this project will examine osteocyte control of osteoblast function from a dynamic perspective. The overall hypothesis is that osteocytes regulate bone mass through the Wnt/p-catenin signaling pathway by controlling the motile properties and differentiated function of osteoblasts and that this regulatory process is modulated by muscle- bone crosstalk and is impaired during aging, leading to a compromised skeleton. To address this hypothesis, live cell imaging techniques will be used in young and aged transgenic mouse models expressing fluorescent reporters for osteoblast and osteocyte lineages and GFP-tagged extracellular matiix proteins. The effect of modulation of osteocyte-produced Wnt and sclerostin will be investigated using inhibitors, gene silencing and transgenic approaches. To determine whether crosstalk from muscle alters osteocyte control of osteoblast function, in viti-o models of myoblast differentiation and transgenic and aged models of impaired or enhanced muscle function will be used. These studies may lead to the way to novel therapeutic approaches for preventing loss of bone and muscle mass in the elderiy.
(See Instnictions): Osteoporosis and sarcopenia are diseases of bone and muscle loss that often occur togetiier in the aged population and represent a major public health problem. The goal ofthis research is to determine the molecular and cellular mechanisms that contribute to the co-ordinated development of these conditions. This research may lead to development of new treatment approaches for these diseases.
|Johnson, Mark L (2016) How rare bone diseases have informed our knowledge of complex diseases. Bonekey Rep 5:839|
|Zhu, Meiling; Sun, Ben-Hua; Saar, Katarzyna et al. (2016) Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo. J Bone Miner Res 31:864-73|
|Gorski, Jeff P; Huffman, Nichole T; Vallejo, Julian et al. (2016) Deletion of Mbtps1 (Pcsk8, S1p, Ski-1) Gene in Osteocytes Stimulates Soleus Muscle Regeneration and Increased Size and Contractile Force with Age. J Biol Chem 291:4308-22|
|Duan, Peipei; Bonewald, L F (2016) The role of the wnt/Î²-catenin signaling pathway in formation and maintenance of bone and teeth. Int J Biochem Cell Biol 77:23-9|
|Maurel, Delphine B; Duan, Peipei; Farr, Joshua et al. (2016) Beta-Catenin Haplo Insufficient Male Mice Do Not Lose Bone in Response to Hindlimb Unloading. PLoS One 11:e0158381|
|Brotto, Marco; Bonewald, Lynda (2015) Bone and muscle: Interactions beyond mechanical. Bone 80:109-14|
|Prideaux, Matthew; Dallas, Sarah L; Zhao, Ning et al. (2015) Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms. PLoS One 10:e0125731|
|Lara-Castillo, N; Kim-Weroha, N A; Kamel, M A et al. (2015) In vivo mechanical loading rapidly activates Î²-catenin signaling in osteocytes through a prostaglandin mediated mechanism. Bone 76:58-66|
|Johnson, Mark L (2015) Unlocking the sost gene. J Bone Miner Res 30:397-9|
|Mo, Chenglin; Zhao, Ruonan; Vallejo, Julian et al. (2015) Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation. Cell Cycle 14:1507-16|
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