The Role Of Osteopontin In Osteoporosis

Osteoclasts (OCs) are bone resorbing multinucleated cells (MNCs) derived from the monocyte/macrophage lineage and plays a key role in many osteopenic disorders, such as osteoporosis, periodontitis, and arthritis. Many researches have indicated that differentiation and function of OCs is regulated by the RANK/RANKL/OPG system, which dictates the quantity of bone resorbed.Osteopontin (OPN; "bone-bridging" protein), is one of the more abundant non-collagenous proteins in bone matrix that is produced by osteoblasts and OCs. OPN has been linked to many physiological and pathological events, including bone remodeling, cancer and inflammation. The much higher expression of OPN at the site of pathology in several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease, has focused attention on this molecule as a potentially critical factor in pathogenesis Recently, extensive studies provide important evidence indicating a role for OPN in the pathogenesis of inflammatory arthritis and associated joint destruction.Although OPN does not appear to be required for normal development of bones, in murine collagen-induced arthritis (CIA), OPN was detected in synovial tissues and at sites of osteoclast-mediated bone resorption. Given the important role of OPN in bone remodeling, such studies about a direct role of OPN in bone erosion would be of great interest.Although extensive studies showed that osteopontin (OPN) is important for bone formation and remodeling, the therapeutic effect of targeting OPN in bone loss disease and the molecular mechanism of OPN action remain largely unknown. Here, anti-OPN mAb (23C3) could inhibit inflammation-induced bone erosion and protect against ovariectomy-induced bone loss in mice. In vitro, opn deficiency or anti-OPN mAb suppressed RANKL-induced osteoclast differentiation and their bone resorptive activity, which was associated with reduced ability of osteoclast attachment, migration, and survival. Furthermore, we found that OPN regulate osteoclast formation and function through RANK/TRAF6-dependent signaling pathway. Interaction of OPN and CD44 was involved in osteoclast formation, whereas OPN promoted bone resorption through binding with integrin. Importantly, it was evident that OPN contributed to the bone loss of patients with rheumatoid arthritis, and OPN regulating mode in human osteoclastogenesis and osteoclast activity was conserved as in murine. Thus, the study has important implications for understanding the role of OPN in osteoclast formation and function, and OPN antagonists may have therapeutic potential for the treatment of osteoporosis and other bone diseases.