Molecular and functional biology of osteoporosis

Research focus:

Our functional studies focus on the molecular mechanisms by which genes of interest are involved in postnatal bone homeostasis, particularly, on their physiophathological roles in osteoporosis.

Osteoporosis is a common skeletal disease that is characterized by progressive and age-dependent bone loss and a consequent increased risk of fragile fractures. Approximately 10 million American women have osteoporosis which causes significant morbidity and mortality. Osteoporosis results from an imbalance where overactive bone resorption exceeds declined bone formation.  The most compelling clinical need for osteoporosis, at the present time, is a therapeutic intervention that rebuilds bone that has already been lost, perhaps over decades, by stimulating bone formation, and, can be used in conjunction with inhibitors of bone resorption.


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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

Hedgehog signaling has been demonstrated important for skeletal development. In vertebrates, the hedgehog signaling is mediated by transcriptional factor Gli proteins, including Gli2 and Gli3, whose activities are regulated by proteasomal processing. In the absence of hedgehog signaling, Gli2 is completely degraded and Gli3 is cleaved into a C' terminal truncated form. When the signaling is initiated, this proteolytic processing of Gli2 and Gli3 is blocked. In vivo and in vitro studies have shown that full-length Gli2 and truncated Gli3 are the predominant functional forms of the Gli family that mediate Hh signaling to target genes.



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

 Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. PTH signaling is mediated through 5'-cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and cAMP response element binding protein (CREB) pathway. PTH binds to a PTH receptor and induces formation of cAMP, leading to activation of PKA, which in turn phosphorylates and activates CREB, a member of a large family of basic leucine zipper (bZIP) domain DNA-binding proteins. Activated CREB, in association with the other co-activators, binds to target genes through a cAMP response element (CRE) and activates their transcription. Therefore, in this pathway, CREB plays a pivotal role by converting the PTH signal to activation of gene expression. However, the transcriptional mechanisms or major downstream targets of CREB transactivation responsible forthe anabolic effects of PTH on osteoblast differentiation and bone formation need to be elucidated.



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 US. Periodontitis affects ~35% of the US adults over the age of 30 years.

Endothelial nitric oxide synthase (eNOS) eNOS catalyzes synthesis of free radical nitric oxide (NO) in cells.  Over the past a couple of decades, the effects of NO on bone metabolism have been convincingly documented. Our in vivo and in vitro and other studies have demonstrated that eNOS plays an important role in osteoblast differentiation and postnatal bone formation. This is supported by the following findings: 1) eNOS is the most widely expressed isoform of the NOS family in bone; 2) eNOS null mice develop a marked osteopenic phenotype due to impaired osteoblast function, and 3) drugs that activate eNOS activity, or mimic the eNOS product nitric oxide (NO), stimulate BMP2 expression in osteoblast cells and induce new bone formation.  In addition, recently, SIRT1, a mammalian member of the Sirtuin longevity protein family which has a variety of anti-aging benefits in many species, was identified as an upstream activator of eNOS.  In our preliminary studies, we found that SIRT1 which activates eNOS in osteoblasts is necessary for postnatal bone mass, as deletion of the SIRT1 gene causes significant bone loss in mice. 



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.

Using genetically deficient eNOS and SIRT1 mouse models, we are determining the precise role of this pathway in maintaining postnatal bone mass, particularly during bone aging, and the molecular mechanisms by which eNOS transactivates BMP2 gene expression in bone.














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