Role of Bone Morphogenetic Protein-2 in Primary Osteoarthritis

Abstract

Osteoarthritis (OA) is a complex, disabling, chronic degenerative joint disease that affects more adults globally than any other rheumatic disease. It leads to joint pain, stiffness and loss of function predominantly in the knees, hips, hands and spine. OA is incurable and at present most treatments, which include physiotherapy, life-style modifications, pharmacotherapy and surgery, aim to provide symptomatic relief rather than targeting the disease process itself. The disease is characterized by two main features: the progressive damage of articular cartilage and bone remodeling or new bone formation (osteophytes and subchondral sclerosis).Several of these bone changes take place not only during the final stage of the disease, but also at the onset of the disease possibly before cartilage degradation. Osteophytes serve as a useful radiographic marker of OA initiation and progression. They are thought to be formed through the process of endochondral ossification and thus involve chondrogenesis and subsequent ossification, the cells responsible are mainly derived from precursor cell in the periosteum and growth factors of the transforming growth factor beta (TGF- ß) superfamily appear to play a crucial role in their induction. The bone morphogentic proteins are subset of the (TGF- ß) superfamily. Although other growth factors such as fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) can be found in bone and have various effects on bone and cartilage cells in vitro, only BMPs have been demonstrated to induce either cartilage or bone formation in vivo. They are produced by mesenchymal cells, osteoblasts and chondrocytes and thought to be key regulators of embryonic skeletogenesis, fracture repair, bone regeneration, endochondral ossification and bone remodeling Bone morphogenetic protein-2 (BMP-2) has been proposed to be one of the most potent inducers of mesenchymal cell differentiation to osteoblasts, while the remaining BMPs promote the maturation of committed osteoblasts. Moreover, BMP-2 controls the expression of several other BMPs and when its activity is blocked, marrow stromal stem cells fail to differentiate into osteoblasts. Chondrocyte metabolism, survival, proliferation and differentiation are tightly controlled by several signaling pathways which are also involved in controlling and promoting new bone formation. In normal adult healthy cartilage, chondrocytes are in a quiescent phase characterized by a fine balance between synthetic activity of the ECM and the production of catabolic enzymes. The histological process of OA development and progression is associated with the differentiation of a variable number of chondrocytes into hypertrophic chondrocytes, which are characterized by the expression and production of collagen X and MMP13. The differentiation process is controlled by some very stringent signaling pathways, among which the molecules of the BMPs family play a prominent role. Elevated BMP levels in damaged cartilage can on one side contribute to tissue repair by boosting matrix synthesis but on the other side stimulate cartilage degeneration by altering chondrocyte behavior and stimulating MMP-13 expression. The present study was carried out to determine the plasma levels of BMP-2 in patients with primary OA and to investigate its relation to disease severity. The study included 30 patients with primary knee OA, their ages ranged from 44-70 and their disease duration ranged from 1-17 years. Seven apparently healthy asymptomatic individuals matched for age and sex served as control group. All patients and controls were subjected to full medical history, pain intensity for the patients was determined using the Numerical Pain Rating Scale (NPRS) as well as assessment of functional status using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), clinical examination, and laboratory investigations included CBC, ESR, CRP, serum uric acid, alkaline phosphatase, kidney and liver function tests, FBS, and RF. Plasma levels of BMP-2 was measured using direct ELISA technique. Plain x-rays for both knees were done to assess the radiological severity of the disease using K-L grading system.