Osteoprotegerin Reduces Osteoclast Numbers and Prevents Bone Erosion in Collagen-Induced Arthritis

Abstract

Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though synovitis is not affected. These findings indicate the potential utility of disrupting RANK signaling to preserve skeletal integrity in inflammatory arthritis.

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

“…Third, serum parameters of bone metabolism reflect an increased bone resorption as the major cause for RA-associated generalized bone loss (14,(19)(20)(21). And, fourth, the roles of RANKL-RANK interaction and osteoclasts in local bone erosion of inflammatory arthritis and the therapeutic efficacy of RANKL/RANK blockade in this respect have been increasingly established (29)(30)(31)(32)(33)(34)(44)(45)(46), providing evidence of a propensity for osteoclasts to become activated in RA. The data reported herein support the concept that hTNFtg mice experience not only a severe destructive arthritis, but also a severe generalized bone loss as a consequence of TNF overexpression.…”

“…Osteoprotegerin (OPG) is a naturally occurring decoy receptor of RANKL and blocks its action by preventing RANKL-RANK interaction (28). The efficacy of OPG and other forms of blocking RANK signaling to inhibit local bone erosion without reducing inflammation has been demonstrated in different animal models of arthritis (29)(30)(31)(32)(33)(34). We recently demonstrated that OPG inhibits local bone erosion in the joints of mice transgenic for human TNF (hTNFtg), which mimics human RA by the spontaneous development of a progressive and destructive polyarthritis (31).…”

Expression and function of RANK in human monocyte chemotaxis

“…It was previously shown that OPG expression on macrophage-type synovial lining cells as well as endothelial cells is deficient in RA patients with active synovitis (18). OPG administration reduced osteoclast numbers and bone erosions in collagen-induced arthritis (15).…”

“…The effects are mediated through RANKL, a member of the tumor necrosis factor superfamily that is expressed on osteoblast/stromal cells and activated T cells (13,14). RANKL exists as a membrane-bound peptide, a soluble fragment cleaved from the cell surface, and a secreted protein (15). Osteoprotegerin (OPG) is a secreted decoy receptor that binds and thereby inactivates RANKL (16).…”

Bisphosphonates: Environmental protection for the joint?

“…Although there has been controversy regarding the cellular mechanisms involved in the pathogenesis of focal articular bone erosions, multiple lines of evidence now support the concept that this process is dependent on osteoclasts. The most compelling data are derived from recent studies in 3 animal models of inflammatory arthritis with different pathogenic mechanisms in which inhibition of osteoclast formation and activation resulted in marked attenuation of focal bone erosions (1)(2)(3). In these studies, the biologic activity of RANKL, an essential factor for osteoclast differentiation, was blocked with osteoprotegerin (OPG), a soluble RANKL receptor.…”