Osteoporosis is a leading public health problem that is characterized by reduced bone mass and bone mineral density. Wnt signaling promotes postnatal bone mass accrual. Our long-term goal is to elucidate the molecular mechanisms underlying the anabolic effects of Wnt signaling pathway on bone. We hypothesize that, in osteoblasts, 1) Wnt signaling regulates mTOR (mammalian homolog of target of rapamycin) activity, an essential serine/threonine kinase that plays a central role in regulating protein synthesis and cell growth; and 2) mTOR plays a critical role in mediating Wnt's anabolic effects on bone. These hypotheses are based on: 1) our biochemical analyses have demonstrated that the Wnt signaling pathway regulates mTOR activity in non-osteoblasts both in vivo and in vitro; and 2) both autosomal dominant high bone mass disease (HBM) and tuberous sclerosing bone dysplasia (TSC) are featured by osteoblastic and osteosclerotic changes in skeletal and craniofacial bones, thus both having being classified to sclerosing bone dysplasia; in these two diseases, hyperactivity of Wnt and mTOR signaling are implicated, respectively. The similar clinical and pathohistological features of these two diseases suggest a possible functional linkage between Wnt and mTOR signaling.
The Specific Aims are:
Aim 1 : Determine whether Wnt signaling promotes mTOR activity in bone, both in vivo and in vitro.
Aim 2 : Elucidate the underlying mechanisms by which Wnt signaling regulates mTOR activity.
Aim 3. Determine whether mTOR is required for Wnt anabolic effects on bone. ; Successful completion of these specific aims will 1) shed critical insight into the molecular mechanism of Wnt signaling' anabolic effects on bone, 2) provide a logical explanation for the similar clinical and pathohistological features shared by two subtypes of sclerosing bone dysplasias, i.e. HBM and TSC bone lesions, and 3) implicates rapamycin, a specific mTOR inhibitor, and the derivatives in treating sclerosing bone diseases caused by hyperactive Wnt signaling.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Shum, Lillian
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Chen, Qian; Liu, Kai; Robinson, Andria R et al. (2013) DNA damage drives accelerated bone aging via an NF-?B-dependent mechanism. J Bone Miner Res 28:1214-28
Xu, Guoshuang; Liu, Kai; Anderson, Judy et al. (2012) Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation. Blood 119:4205-14
Wang, Feng-Ming; Chen, Yi-Jiun; Ouyang, Hong-Jiao (2011) Regulation of unfolded protein response modulator XBP1s by acetylation and deacetylation. Biochem J 433:245-52
Wang, Feng-Ming; Galson, Deborah L; Roodman, G David et al. (2011) Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells. Exp Hematol 39:999-1006
Bennett, Christina N; Ouyang, Hongjiao; Ma, Yanfei L et al. (2007) Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J Bone Miner Res 22:1924-32