Bone Center: Faculty: Ming Zhao, M.D., Ph.D.

Ming Zhao, M.D., Ph.D.
Research Assistant Professor

University of Hebei Medical School, M.D., China
1983
Academy of Military Medical Sciences, Ph.D., China
1993

Zhao Portrait

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(615)
(615)
@vanderbilt.edu

BMP-2 signaling
BMP-2 is a very important bone-inducing growth factor of TGFβ superfamily. BMP-2 stimulates osteoblast differentiation and bone formation during both embryonic skeletogenesis and postnatal bone modeling and remodeling. In our previous studies on BMP-2 signaling, we demonstrated that type I and type II receptors play critical roles in mediating BMP-2 effect in bone. We found that overexpression of dominant negative type IB BMP receptor (dnBMPR-IB) in transgenic mice results in significant retardation of skeletogenesis in embryos and inhibition of bone formation in adult mice. We also found that type IIB Activin receptor is required for BMP-2 signaling for osteoblast differentiation. In addition to BMP receptors, BMP signaling cascade involves many downstream signal molecules, including transcription factors Smad1, Smad1 and Runx2. Recently, we have demonstrated that a specific E3 ubiquitin ligase, Smurf1, not only mediates proteolytic processing of Smads, but also is responsible for the modulation of Runx2 degradation. Runx2 is a critical bone-forming transcription factor. Runx2 null mutation results in total bone loss in embryo. In the transgenic mice, overexpression of Smurf1 significantly inhibits osteoblast differentiation and bone formation.

Research Image

BMP-2 gene regulation
BMP-2 gene expression in bone is regulated under various physiological or pathological circumstances, such as aging. However, the mechanisms by which BMP-2 gene transcription is regulated have not been well identified. Currently, we have two ongoing projects focusing on the transcriptional regulation of BMP-2 gene expression which are currently supported by NIH R03, R01 and K01 grants.

The roles of Gli zinc finger proteins in BMP-2 gene regulation.
Gli family including Gli1, Gli2 and Gli3 are transcriptional factors that mediate Shh signaling. Gli2 and Gli3 null mutations cause severe skeletal abnormalities in embryonic development. Our in vitro and in vivo data demonstrated that Gli2 is a powerful activator of BMP-2 gene while truncated Gli3 serves as a powerful repressor. Loss-of-function of Gli2 substantially impairs osteoblast differentiation and endochondral bone formation. By the promoter assays, we have identified the interaction elements in the promoter which are responsible for Gli2 transactivation.

The effects of Wnt/β-catenin on the regulation of BMP-2 gene transcription.
Genetic studies have shown that disruption of Wnt signaling results in marked bone loss. Nuclear protein β-catenin mediates Wnt signal to the target genes including bone specific genes. Recently, we found β-catenin dramatically up-regulates BMP-2 gene transcription and subsequent osteoblast differentiation. Our data suggest that the transactivation of BMP-2 gene by β-catenin is likely indirect. We are now identifying the mechanism by which β-catenin regulates BMP-2 gene transcription.

Skeletal aging
Moreover, we are also interested in skeletal aging. Osteoporosis, a clinical skeletal aging, is a common disease associated with severe bone loss and microarchitectural deterioration leading to increased bone fragility and increased risk of fracture. The mechanisms of skeletal aging are not entirely clear, but likely relate to decreased availability or effects of bone growth factors. BMP-2 is recently recognized as an osteoporosis-associated gene. Identification of the mechanisms by which BMP-2 gene expression is regulated in aging will lead to insight of the molecular mechanisms of bone anabolic regulation especially in age-related bone morphology, and provide a potential target for the treatment of clinical senile ostoepenia. Recently, we found that SAMP6 mice (senescence-accelerated mouse) develop accelerated skeletal aging characterized by severe earlier bone loss starting from 5 month old, with a significant reduction of BMP-2 gene expression in bone. Since short Gli3 (sGli3), which is a C’ terminal truncated product of Gli3, is a powerful repressor of many bone-related genes including BMP-2 gene, we hypothesize that the proteolytic processing that produces repressor sGli3 is accelerated resulting in inhibition of bone-forming gene expression and consequent bone loss. The hypothesis is now being tested.

Research Techniques:
Analysis of animal skeletal phenotype
Analysis of osteoblast differentiation
Bone-specific transgenic mouse models
Promoter studies: reporter assay, EMAS, CHIP

Recent Publications:

M Zhao, M Qiao, SE Harris, BO Oyajobi, GR Mundy, D Chen. (2004) Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. J. Biol. Chem, 279(13): 12854-12859

M Zhao, M Qiao, BO Oyajobi, GR Mundy, D Chen. (2003) E3 Ubiquitin ligase Smurf1 mediates Cbfa1 degradation and plays a specific role in osteoblast differentiation. J. Biol. Chem, 278(30): 27939-27944

IR Garrett, D Chen, G Gutierrez, M Zhao, A Escobedo, G Rossini, SE Harris, W Gallwitz ,KB Kim, S Hu, CM Crews, GR Mundy. (2003) Selective Inhibitors of the Chymotrypsin-like Activity of the Osteoblast Proteasome are Potent Stimulators of Bone Formation in Vivo and In Vitro. J. Clinical Investigation, 111(11): 1771-1782

M Zhao, SE Harris, D Horn, ZP Geng, R Nishimura, GR Mundy, D Chen. (2002) Bone Morphogenetic Protein Recaptor Signaling Is Necessary for Normal Murine Postnatal Bone Formation. J Cell Biology, 157(6):1049-60

G Mundy, R Garrett, S Harris, J Chan, D Chen, G Rossini, B Boyce, M Zhao, G Gutierrez.(1999) Stimulation of Bone Formation in vitro and in Rodents by Statins. Science, 286(3):1946-50

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