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3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions.

ABSTRACT: A fine balance between bone resorption by osteoclasts and bone formation by osteoblasts maintains bone homeostasis. In patients with cherubism, gain-of-function mutations in 3BP2, which is encoded by SH3-domain binding protein 2 (SH3BP2), cause cystic lesions with activated osteoclasts that lead to craniofacial abnormalities. However, little is known about the function of wild-type 3BP2 in regulating bone homeostasis. Here we have shown that 3BP2 is required for the normal function of both osteoblasts and osteoclasts. Initial analysis showed that Sh3bp2-/-mice developed osteoporosis as a result of reduced bone formation despite the fact that bone resorption was impaired. We demonstrated using reciprocal bone marrow chimeras, a cell-intrinsic defect of the osteoblast and osteoclast compartments in vivo. Further, Sh3bp2-/- osteoblasts failed to mature and form mineralized nodules in vitro, while Sh3bp2-/- osteoclasts spread poorly and were unable to effectively degrade dentine matrix in vitro. Finally, we showed that 3BP2 was required for Abl activation in osteoblasts and Src activation in osteoclasts, and demonstrated that the in vitro defect of each cell type was restored by the respective expression of activated forms of these kinases. These findings reveal an unanticipated role for the 3BP2 adapter protein in osteoblast function and in coordinating bone homeostatic signals in both osteoclast and osteoblast lineages.

SUBMITTER: Levaot N

PROVIDER: S-EPMC3148735 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions.

Levaot Noam N Simoncic Paul D PD Dimitriou Ioannis D ID Scotter Andrew A La Rose Jose J Ng Adeline H M AH Willett Thomas L TL Wang Chiachien J CJ Janmohamed Salima S Grynpas Marc M Reichenberger Ernst E Rottapel Robert R

The Journal of clinical investigation 20110718 8

A fine balance between bone resorption by osteoclasts and bone formation by osteoblasts maintains bone homeostasis. In patients with cherubism, gain-of-function mutations in 3BP2, which is encoded by SH3-domain binding protein 2 (SH3BP2), cause cystic lesions with activated osteoclasts that lead to craniofacial abnormalities. However, little is known about the function of wild-type 3BP2 in regulating bone homeostasis. Here we have shown that 3BP2 is required for the normal function of both osteo ...[more]

PMID: 21765218

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Project description:Most US Food and Drug Administration (FDA)-approved treatments for osteoporosis target osteoclastic bone resorption. Only PTH derivatives improve bone formation, but they have drawbacks, and novel bone-anabolic agents are needed. Nitrates, which generate NO, improved BMD in estrogen-deficient rats and may improve bone formation markers and BMD in postmenopausal women. However, nitrates are limited by induction of oxidative stress and development of tolerance, and may increase cardiovascular mortality after long-term use. Here we studied nitrosyl-cobinamide (NO-Cbi), a novel, direct NO-releasing agent, in a mouse model of estrogen deficiency-induced osteoporosis. In murine primary osteoblasts, NO-Cbi increased intracellular cGMP, Wnt/β-catenin signaling, proliferation, and osteoblastic gene expression, and protected cells from apoptosis. Correspondingly, in intact and ovariectomized (OVX) female C57Bl/6 mice, NO-Cbi increased serum cGMP concentrations, bone formation, and osteoblastic gene expression, and in OVX mice, it prevented osteocyte apoptosis. NO-Cbi reduced osteoclasts in intact mice and prevented the known increase in osteoclasts in OVX mice, partially through a reduction in the RANKL/osteoprotegerin gene expression ratio, which regulates osteoclast differentiation, and partially through direct inhibition of osteoclast differentiation, observed in vitro in the presence of excess RANKL. The positive NO effects in osteoblasts were mediated by cGMP/protein kinase G (PKG), but some of the osteoclast-inhibitory effects appeared to be cGMP-independent. NO-Cbi increased trabecular bone mass in both intact and OVX mice, consistent with its in vitro effects on osteoblasts and osteoclasts. NO-Cbi is a novel direct NO-releasing agent that, in contrast to nitrates, does not generate oxygen radicals, and combines anabolic and antiresorptive effects in bone, making it an excellent candidate for treating osteoporosis. © 2016 American Society for Bone and Mineral Research.

Dataset Information

3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions.

Publications

3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions.

Similar Datasets

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