Role of angiogenesis in bone and joint diseases

Abstract

within the hypertrophic cartilage is controlled by several genes, including matrix metalloproteinase 9 (MMP-9), the transcription factor Runx2 and connective tissue growth factor (Ctgf). MMP-9 serves to make matrix-bound VEGF available for binding to receptors on target cells; Runx2 affects transcription of the VEGF gene; Ctgf acts downstream of or in parallel with Runx2 to regulate VEGF expression. Osteoclasts, derived from monocytes, are essential for normal vascularization of hypertrophic cartilage and for remodeling of trabecular bone in the metaphyseal region of long bones. VEGF has been found to stimulate differentiation of osteoclasts from monocytes, acting as a co-stimulator with RANKL in addition to enhancing osteoclastic bone resorption activity. VEGF is also critical for survival of chondrocytes in the hypoxic epiphyseal regions of developing long bones. Loss of VEGF in these regions result in massive chondrocyte apoptosis and gross abnormalities in growth plate regions. Finally, osteoblast-generated VEGF is required for normal differentiation of osteoblasts. Loss of VEGF expression in osteoblastic progenitors in mice results in decreased bone density postnatally and increased numbers of adipocytes in bone marrow. Studies of bone marrow cells from such mice indicate that VEGF has a critical role in bone homeostasis by controlling osteoblast precursor numbers and maintaining their osteoblastic fate by preventing adipocyte differentiation.