Osteoclasts are essential for TNF-α–mediated joint destruction

Abstract

The detailed cellular and molecular mechanisms leading to joint destruction in rheumatoid arthritis, a disease driven by proinflammatory cytokines, are still unknown. To address the question of whether osteoclasts play a pivotal role in this process, transgenic mice that express human TNF (hTNFtg) and that develop a severe and destructive arthritis were crossed with osteopetrotic, c-fos-deficient mice (c-fos(-/-)) completely lacking osteoclasts. The resulting mutant mice (c-fos(-/-)hTNFtg) developed a TNF-dependent arthritis in the absence of osteoclasts. All clinical features of arthritis, such as paw swelling and reduction of grip strength, progressed equally in both groups. Histological evaluation of joint sections revealed no difference in the extent of synovial inflammation, its cellular composition (except for the lack of osteoclasts), and the expression of matrix metalloprotein-ase-3 (MMP-3) and MMP-13. In addition, cartilage damage, proteoglycan loss, and MMP-3, -9, and -13 expression in chondrocytes were similar in hTNFtg and c-fos(-/-)hTNFtg mice. However, despite the presence of severe inflammatory changes, c-fos(-/-)hTNFtg mice were fully protected against bone destruction. These data reveal that TNF-dependent bone erosion is mediated by osteoclasts and that the absence of osteoclasts alters TNF-mediated arthritis from a destructive to a nondestructive arthritis. Therefore, in addition to the use of anti-inflammatory therapies, osteoclast inhibition could be beneficial for the treatment of rheumatoid arthritis.

Osteoporosis in inflammatory joint diseases

“…Osteoclasts are found at the interface between synovitis and subchondral bone, and osteoclasts precursors are abundant in the synovium of RA patients. In an osteoclast-deficient animal model, overexpression of TNF leads to chronic inflammatory arthritis, but no bone erosions [61]. The generation of osteoclasts in the synovial tissue allows the penetration in bone through the thin cortical barrier [62].…”

Comparison of anti-arthritic properties of leflunomide with methotrexate and FK506: Effect on T cell activation-induced inflammatory cytokine production in vitro and rat adjuvant-induced arthritis

“…Previously, physical function was not employed very often to evaluate the effects of agents, although inflammatory parameters, and bone and cartilage destruction in this model have been studied in detail. In murine arthritis models, there have been reports assessing grip strength as a surrogate marker of joint function [14,15]. Loss of grip strength and function is a cause of disability in RA patients.…”

Systemic bone effects of biologic therapies in rheumatoid arthritis and ankylosing spondylitis

“…Initially, in collagen-induced arthritis, the articular bone destruction was prevented by osteoprotegerin [45,46]. Then bone destruction induced by overexpressing hTNFα transgenic mice was also prevented by Fc-OPG, Fc-RANK treatment [47][48][49]. In another approach using osteoclast-deficient mice lacking either RANKL or c-Fos, the arthritis phenomenon failed to produce the expected bone destruction.…”