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overview 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. Therefore, we are interested in elucidating the upstream regulatory mechanisms that may underline of the beta-catenin signaling pathway. We are also interested in investigating the possible pathogenic role of beta-catenin deregulation in bone and soft tissue tumors. Furthermore, we are investigating the potential roles of EF-hand calcium-binding S100 proteins in osteosarcoma progression and the development of pulmonary metastasis. Clinically relevant osteosarcoma animal model In order to investigate the pathogenesis of human osteosarcoma, there is a great need to develop a clinically relevant animal model. We have developed such an orthotopic animal model of osteosarcoma using several human osteosarcoma lines. This clinically relevant model of human osteosarcoma provides varying degrees of tumor growth at the primary site and of metastatic potential. Thus, this orthotopic model is being used as a valuable tool to investigate factors that promote or inhibit osteosarcoma growth and/or metastasis. For instance, we are now using this model to investigate the roles of genes that are known to promote cell proliferation and inhibit differentiation, and genes that potentially promote or inhibit cancer metastasis. This orthotopic model can also be used to test anti-tumor small molecules or other targeted therapies. Osteosarcoma is a differentiation disease We believe that understanding the molecular events behind normal osteoblast differentiation of MSCs may provide important clues to osteosarcoma development. Stem cell differentiation and tumorigenesis share some strikingly similar characteristics. Both normal stem cells and cancer stem cells have the ability to self-renew. Although stem cells are often the target of genetic events that are necessary or sufficient for malignant transformation, in some cases restricted progenitors or even differentiated cells may become transformed. Thus, cancer stem cells may be derived from tissue-specific stem cells or progenitors, such as MSCs. Although cancer stem cells for osteosarcoma remain to be identified, OS cells indeed exhibit the characteristics of undifferentiated osteoblasts, and we have shown that differentiation-promoting agents can inhibit OS proliferation. Accordingly, we found that human osteosarcoma cells are in general refractory to osteogenic BMPs and exhibit no signs of terminal differentiation upon osteogenic BMP stimulation. Thus, we hypothesize that osteosarcoma development is caused by molecular/genetic disruptions of the osteogenic differentiation pathway. We are investigating and identifying the possible defects in osteogenic pathway, including the possible roles of the early target genes of BMP-induced osteoblast lineage-specific differentiation of MSCs. MOLECULAR BIOLOGY OF CANCER METASTASIS Cancer metastasis is an often overlooked and least understood problem. Metastasis is defined as the progressive growth of tumor cells at a site that is discontinuous from the primary tumor. Although not an efficient process, colonization at distant tissues by tumor cells represents the most dangerous attribute of cancer, because metastases, rather than primary tumors, are responsible for most cancer deaths. Metastatic cells are a subset of primary tumor cells that have acquired the ability to complete a multi-step metastatic cascade, including migration, dissemination, extravasation, and eventual proliferation at a discontinuous secondary site. Understanding the molecular biology of cancer metastasis may provide novel intervention strategies to control/contain metastatic lesions, and/or to improve the quality of life for the patients with these advanced diseases. Pulmonary metastasis of primary bone tumors Lung metastasis is the leading cause of OS mortality. Our orthotopic tumor model of human OS provides a unique opportunity for us to investigate the molecular events underlying osteosarcoma pulmonary metastasis. Using this model, we have conducted serial selections of highly metastatic human OS sublines, which were otherwise non-metastatic. Using microarray analysis, we have compared the gene expression profiles between these sublines and the parental lines in search for gene(s) that may cause or be associated with osteosarcoma metastasis. In an alternative approach, we are conducting functional selection assays, in which an RNAi library has been introduced into the non-metastatic or less metastatic human osteosarcoma cells to recover lung metastases and to identify potential metastasis suppressors of human osteosarcoma. Metastatic bone tumors Bone is one of the most frequently targeted organs for cancer metastasis, and bone is the most common site for distant relapse of most cancers. The bone microenvironment is unique among metastatic target tissues because it is subjected to continuous remodeling under the influence circulating hormones and local bone-derived factors. Interactions between the bone microenvironment and the cancer cells can give rise to osteolytic (bone resorbing) or osteoblastic (bone forming) metastasis. Osteolytic bone metastasis are characteristic for most malignancies, such as breast cancer and lung cancer, while osteoblastic metastasis is mostly associated with prostate cancer. We are investigating the molecular mechanisms through which the interactions between metastatic (breast and prostate) cancer cells and bone microenvironment are regulated. NOVEL THERAPEUTIC AND/OR PREVENTIVE STRATEGIES FOR BONE AND MUSCULOSKELETAL DISEASES The ultimate goal of biomedical research is to develop innovative diagnostic, therapeutic, and/or preventive strategies for human diseases. We are interested in developing innovative approaches for local or systemic delivery of therapeutic genes as effective treatment for bone and musculoskeletal diseases. We are investigating the use of osteogenic BMPs for bone regeneration, enhancing fracture healing, repairing segmental defects, promoting spinal fusion, and preventing implant wear particle-induced osteolysis. We have recently demonstrated the potential use of some of the BMPs in promoting biomechanical features of healing tendons/ligaments. We also demonstrated that Sox9, a master regulator of chondrogenesis, may be used in gene therapy to treat intervertebral disc degeneration and articular cartilage injuries. These lines of investigation reflect our commitment to the true spirit of translational research in bone and musculoskeletal disorders.

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