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The mechanism for postnatal bone formation, particularly in aging, is of fundamental importance to both basic skeletal biology and clinical management of osteoporosis. Bone morphogenetic protein 2 (BMP2) is known as an extremely important anabolic protein that stimulates osteoblast differentiation and bone formation. However, the precise transcriptional mechanisms that control BMP2 expression in osteoblast cells, particularly during skeletal aging warrant further exploration. Recently, we have identified multiple signaling pathways as important mechanisms responsible for BMP2 gene regulation in osteoblasts. Currently, we are conducting the following studies to fully characterize the roles of these signaling pathways in maintenance of postnatal bone mass through regulating osteoblastogenesis and osteoclastogenesis.
Role of the hedgehog signaling in bone homeostasis
We have demonstrated in vitro that Gli2 and Gli3 are potent regulators of osteoblast differentiation and bone formation. While full-length Gli2 stimulates osteoblast differentiation, truncated Gli3 inhibits osteoblast differentiation and bone formation. Our findings also suggest that the effects of Gli2 and Gli3 on osteoblasts are mediated, at least in part, through BMP2. Full-length Gli2 is a powerful activator of BMP2 transcription, whereas truncated Gli3 acts as a strong BMP2 repressor in osteoblasts. We hence have named the full-length activator Gli2 as Gli2act and the truncated repressor Gli3 as Gli3rep. We hypothesized that Gli2act and Gli3rep play important roles in postnatal bone formation by regulating BMP2 production in osteoblasts, particularly during skeletal aging. Conventional global Gli2 and Gli3 knockout mice do not survive after birth, so we have created osteoblast-specific knockout Gli2act and transgenic Gli3rep mouse models and now we are conducting experiments to test our hypothesis.
Dual functions of microtubule dynamics in osteoblasogenesis and osteoclastogenesis
Cytoskeleton microtubules, composed of tubulins, undergo constant assembly and disassembly, modulation of microtubule dynamics affects their biological function. Previously, we have reported that inhibition of microtubule assembly by microtubule-targeting drugs induces BMP2 expression in osteoblasts and consequent bone formation. Stathmin (also referred as OP18), a small cytosolic phosphoprotein, has been identified as a natural endogenous microtubule regulating protein. Stathmin binds directly to microtubules and disrupts their intrinsic dynamic stability by inhibiting assembly and promoting disassembly. We found that stathmin knockout mice develop an osteopenic phenotype low bone mineral density (BMD) and trabecular bone volume. Further characterization showed that the low bone mass is caused by inhibition of osteoblast differentiation and activation of osteoclast formation in bone. In osteoblasts, we found that stathmin KO inhibited Gli2-induced BMP2 transcription. Furthermore, immunofluorescent studies have shown that stathmin functions in both osteoblasts and osteoclasts by affecting microtubule network structure in these cells. These results suggest that microtubule dynamics is potential target for development of novel dual-function drugs that inhibit osteoclastic bone resorption and stimulate osteoblastic bone formation. Currently, we are fully characterizing bone phenotype of stathmin KO mice.
Transcriptional regulation of CREB on BMP2 gene in bone
Our in vivo studies on global and osteoblast-specific CREB knockout mice have shown that deficiency of CREB results in significant reduction in bone mass which is caused by inhibition of osteoblast differentiation. In vitro, we found that demonstrated that PTH signaling that activates CREB by phosphorylation promotes osteoblastic differentiation, and that the PTH-CREB signaling pathway functions as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affects BMP2 transcription through a specific CRE in the BMP2 promoter. These results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts. Now, we have an ongoing study to determine the effects of CREB deficiency on the anabolic effects of intermittent administration of PTH on bone mass in the CREB knockout mice.
eNOS longevity activity and bone quality
Periodontitis, characterized by progressive loss of periodontal attachment and alveolar bone, is one of the most prevalent chronic diseases and a major cause for loss of permanent teeth in the
We also found that resveratrol, a natural anti-aging nutrient and a known powerful stimulator of SIRT1, induces SIRT1 and eNOS gene expression and enhances eNOS enzymatic activity in osteoblast cells. Therefore, we reason that the longevity factor, SIRT1, is a key upstream activator of eNOS in osteoblast cells. These findings suggest that the eNOS pathway could be a potential target for drug development that stimulate bone formation.
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