Role of bone morphogenic protein in osteoarthritis

Abstract

BMPs are members of the TGFb superfamily. The activity of BMPs was first identified in the 1960s by Urist but the proteins responsible for bone induction remained unknown until the purification and sequence of bovine BMP-3 (osteogenin) and cloning of human BMP-2 and 4 in the late 1980s. BMPs are morphogenetic proteins, namely, molecules which induce the genome to initiate the formation of a morphogenetic area &altering the developmental process. The structure of more than sixteen different human BMPs has been identified with the aid of molecular biology techniques . The BMPs are designated as BMP-1 to BMP-16 and are divided into several subtypes, according to structural similarity between the molecules within each subfamily. BMPs consist of dimers with two polypeptide chains held together bya single disulfide bond, BMPs are synthesized as precursor proteins with an N-terminal signal peptide, a prodomain for folding and secretion, and a C-terminal mature peptide. BMPs bind to two type of receptors type I and type II,Three type I receptors have been shown to bind BMP ligands, type IA and IB BMP receptors and type IA activin receptor,Three type II receptors for BMPs have also been identified and they are type II BMP receptor (BMPR-II) and type IIA and IIB activin receptors . Bone morphogenetic proteins (BMPs) have been implicated in a variety of functionsduring foetal development. BMPs induce the formation of both cartilage and bone. BMP2, 4, 6, 7, and 9 are commonly referred to as the osteogenic BMPs, based on their potent bone-inducing activity. BMPs induce synoviocyte and MSC proliferation, drive chondrogenic differentiation ,stimulate chondrocyte to synthetize proteoglycans, aggrecan and type II collagen, and decrease the catabolic effects of cytokines such as interleukin-1 (IL-1) and the matrix metalloproteinases Invitro data indicate BMP-2 stimulates matrix synthesis and interestingly is capable of reversing chondrocyte differentiation to some extent as indicated by an increase in synthesis of cartilage-specific collagen type IIB in chondrocytes. The effect of BMP-2 on MSCs is similar to that of TGF-β1 with increased Extracellular matrix production and decreased expression of collagen type 1 When injected into murine knees, chondrophytes induced by BMP-2 were found in the location where the growth plates meet the joint space. Healing of long bone critical-sized defects by BMP-2 has been demonstrated in species including rats, rabbits, dogs, sheep and non-human primates. Systemic administration of rhBMP-2 increases mesenchymal stem cell activity and reverses ovariectomy-induced and age-related bone loss in two different mouse models. BMP-7 or osteogenic protein-1 (OP-1) exhibits the most convincing effects. It is the only BMP studied thus far in adult cartilage that demonstrates strong anabolic activity in vitro and in vivo with and without serum. OP-1 stimulates the synthesis of the majority of cartilage extracellular matrix proteins in adult articular chondrocytes derived from different species and of different age. OP-1 counteracts the degenerative effect