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I direct the Molecular Oncology Laboratory in the Department of Orthopaedic Surgery and Rehabilitation Medicine. Our lab consists of a dynamic group of basic science investigators and physician scientists, who have diverse expertise and a broad range of research interests. Our shared long-term objective is to better understand the molecular pathogenesis of bone and musculoskeletal diseases and to translate basic discoveries into potential therapies and/or preventive measures in clinical settings. Specifically, we focus on the following areas: LINEAGE COMMITMENT AND TERMINAL DIFFERENTIATION OF MESENCHYMAL STEM CELLS (MSCS) Multipotency of MSCs MSCs are pluripotent and capable of differentiating into osteogenic, chondrogenic, myogenic or adipogenic lineage. Understanding the molecular mechanisms of bone formation is pivotal for studying the pathogenesis of bone diseases. We are interested in elucidating the molecular mechanisms through which regulate the proliferation and differentiation of osteoblasts, chondrocytes, and adipocytes. Both Wnt/beta-catenin and bone morphogenetic proteins (BMPs) have been considered as important regulators of osteogenic differentiation of mesenchymal stem cells. We are investigating the biological functions of BMPs and Wnt/beta-catenin signaling in regulating the osteoblast differentiation of MSCs. We have therefore conducted a comprehensive analysis of BMP and Wnt3A-induced osteoblast differentiation of MSCs. Our findings indicate that osteoblast differentiation is a well-regulated process in normal progenitor cells, while osteosarcoma cells are refractory to osteogenic differentiation signal. BMP-9 is one of the most potent regulators of osteogenic differentiation The bone-forming osteoblasts are derived from pluripotent bone marrow fibroblasts (a.k.a., MSCs). Although the molecular mechanisms underlying bone formation remain to be defined, BMPs seem to play an important role in osteoblast differentiation. At least 15 types of BMPs have been identified in mice and humans. However, the ability of BMPs to induce osteoblast differentiation of mesenchymal stem cells has not been comprehensively investigated, mostly due to the fact that recombinant proteins are either not biologically active or not available for all BMPs. Through a comprehensive analysis, we found that BMP2, BMP6, and BMP9 (to a much lesser extent, BMP4 and BMP7) exhibited the greatest ability to induce osteoblast differentiation, whereas BMP3 was shown to inhibit osteogenesis, both in vitro and in vivo. Our findings about BMP9 as one of the most potent inducers of osteoblast differentiation are novel and particularly intriguing because BMP9 is one of the least characterized BMPs and its functions are largely unknown. Thus, many questions regarding BMP9 signaling need to be answered: What are the type I and type II TGFbeta/BMP receptors involved in BMP9 binding? What Smads are required for BMP9 signaling? How are the downstream targets regulated by BMP9? More importantly, what are the roles of BMP9 during embryonic and/or skeletal development? We are interested in addressing these questions. Critical mediators of BMP-induced differentiation of MSCs We have identified several potentially important signaling mediators of BMP-induced osteogenic differentiation. These targets include the Inhibitors of DNA binding/Differentiation helix-loop-helix (a.k.a., Id proteins) and CTGF. Interestingly, both Ids and CTGF have been shown to overexpress in human tumors. Our findings suggest that Ids and CTGF may play an important role in promoting the proliferation of early osteoblast progenitor cells and that their expression must be down-regulated during the terminal differentiation of committed osteoblasts, suggesting that a balanced regulation of their expression may be critical to BMP-induced osteoblast lineage-specific differentiation of MSCs. We are currently dissecting the functional roles of the important downstream mediators in BMP-induced osteogenic signaling. We are also interested in identifying the molecular switches that control the lineage-specific differentiation of osteoblasts, chondrocytes, and adipocytes in MSCs. We are especially interested in understanding at what stage osteogenic BMPs (e.g., BMP2 or BMP9)-induced osteogenic and adipogenic differentiation diverges. What are the potential regulators that control this lineage divergence? It has been long postulated that a disrupted balance between osteogenesis and adipogenesis may cause musculoskeletal diseases, such as osteoporosis. Wnts regulate osteogenic differentiation of mesenchymal stem cells Our earlier studies demonstrated that Wnt/beta-catenin signaling is de-regulated in over 70% of human osteosarcoma. Recent studies also suggest that Wnt signaling may play an important role in regulating bone density, and one of the Wnt signaling antagonists Dkk1 may be implicated in the development of osteolytic lesion in multiple myeloma patients. We demonstrated that Wnt3A can induce the early osteogenic marker alkaline phosphatase in MSCs. Upon analyzing the gene expression profile of MSCs that were stimulated with Wnt3A, we found that three members of the CCN family, CCN1/Cyr61, CCN2/CTGF, and CCN5/WISP2, were among the most significantly up-regulated genes. Further studies demonstrate that CTGF is a mutual target of Wnt and BMP-9, and plays an important role in regulating osteogenic differentiation. However, more questions remain to be answered. We are currently investigating how osteogenic differentiation of MSCs is regulated by canonical and non-canonical Wnt signaling. MOLECULAR BASES OF BONE AND SOFT TISSUE SARCOMAS Sarcomas represent a heterogeneous group of malignant mesenchymal tumors with numerous histologic subtypes and complex cytogenetic abnormalities. Unlike other common solid tumors, sarcomas are relatively uncommon and their molecular pathogenesis, in general, are poorly understood. We mainly focus on understanding the molecular biology of primary bone tumor (a.k.a., osteosarcoma, OS). Osteosarcoma is the most common primary malignancy of bone, and is among the most common non-hematological primary tumors of bone in both children and adults. The peak incidence occurs in the second decade. With preoperative chemotherapy, the five-year survival rate of patients with non-metastatic tumors has improved significantly to approximately 60-70%. However, cases with local recurrence and/or pulmonary metastasis are usually less sensitive, if not resistant, to conventional chemotherapies. Several cytogenetic studies suggest that certain chromosomal regions may be amplified, rearranged, or deleted in some, but not all, human osteosarcomas. Unfortunately, the low incidence of this disease and the absence of any familial predisposition have complicated efforts to identify osteosarcoma-associated genes. Thus, we are taking a comprehensive approach to elucidate the molecular mechanisms underlying the development of osteosarcoma. Wnt/beta-catenin signaling in the development of human osteosarcoma Aberrant activation of Wnt/beta-catenin signaling by inactivating APC tumor suppressor or oncogenic activation of beta-catenin plays an important role in colorectal tumorigenesis. Oncogenic activation of beta-catenin has also been reported in several types of human solid tumors. We found that beta-catenin signaling is de-regulated in about 70% of human osteosarcoma without beta-catenin mutations. As in many other types of non-colon cancer, little is known about how Wnt/beta-catenin signaling pathway is activated.
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AMERICAN JOURNAL OF TRANSLATIONAL RESEARCHno. 9 (2023): 5959-5960
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