Bone repair after injury or surgery is a specialized type of wound repair response in which bone is regenerated for the purpose of supporting mechanical loads. While the process of bone repair is usually considered to be biologically optimal, the healing of five to ten percent of the estimated 6.2 million fractures occurring annually in the United States is delayed or impaired. Thus, to reduce the morbidity associated with fractures, and to provide better control over the healing responses associated with other reconstructive orthopedic procedures, an improved understanding of the biology of bone healing is required. Numerous studies have focused on cytokines as mediators of skeletal repair. Cytokines can be grouped into three subfamilies: cysteine-knot growth factors, helical cytokines and tumor necrosis factors. The tumor necrosis factors (TNF) family of cytokines has been shown to be essential in the mediation of bone remodeling. We have demonstrated that transgenic mice deficient in both the p55 and p75 TNF-alpha receptors show delayed bone repair, an absence of intramembranous bone formation but enhanced endochondral bone formation and a failure in the removal of endochondral cartilage. The central hypothesis of this proposal is that TNF-alpha provides key regulatory signals that control the resorption of calcified cartilage and regulates the progression of osteogenesis during of endochondral skeletal tissue repair. The goal of this proposal is to determine the cellular and molecular mechanisms by which TNF-alpha mediates these functions in bone repair.
Aim 1 addresses two interrelated goals. The first is to define how key biological processes and cellular functions are altered in the absence of both receptors during fracture repair. Rates and amounts of skeletal cell differentiation and maturation, rates of cellular proliferation and apoptosis, processes of tissue resorption, and processes of tissue vascularization will be assessed at cellular and molecular levels in vivo. The second goal of Aim 1 is to define the functional roles of the individual TNF-alpha receptors (p55 or p75) during bone repair, by assessing fracture repair in transgenic mice in which these receptors have been separately ablated.
Aim 2 has two goals. The first is to define the molecular mechanisms by which TNF-alpha mediates hypertrophic chondrocyte apoptosis. The second goal is to determine the molecular mechanisms by which TNF-alpha functions as a central paracrine/autocrine factor that is regulating the progression of mesenchymal cell differentiation into osteogenic or chondrogenic cells.
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