Lupus IgG deposition causes arthritis but inhibits bone destruction through competitive occupation of FcγRI and reduced RANKL signalling

Abstract

Objectives. Bone destruction is a remarkable feature of inflammatory arthritis. It remains unknown why arthritis associated with the systemic autoimmune/inflammatory condition systemic lupus erythematosus (SLE) does not result in erosion and destruction. We aimed to determine the role of autoantibody in the pathogenesis of non-erosive arthritis in SLE. Methods. We analysed medical record of SLE patients, investigated whether autoantibody induces arthritis lacking bone destruction in animal models and determined whether SLE autoantibody inhibits osteoclastogenesis induced by RANKL in vitro experiments. Results. We found that arthritis lacking bone erosions is common in SLE patients and lupus-prone mice. Intraarticular injection of lupus serum or IgG induces immune complex deposition and arthritis, but does not result in bone destruction. Deposition of IgG, monocytes/macrophages and TNF-a is all required for the development of arthritis. Lupus serum or IgG inhibits RANKLinduced differentiation of monocytes into osteoclast in a dosedependent manner. FccR acts as co-receptors for RANKL and is involved in osteoclastogenesis. Deficiency of FccRII or FccRIII does not affect osteoclastogenesis in the presence of SLE IgG. However, lupus IgG competes for FccRI binding with RANKL, thereby reducing osteoclastogenesis. Conclusion. Observations from this study demonstrate that IgG from SLE patients can induce arthritis and inhibits RANKL-induced osteoclastogenesis through competitive occupation of FccRI on monocytes/macrophages. This study improves the understanding of the pathophysiology of SLEassociated arthritis and offers a protective mechanism (FccRI inhibition) that may be targeted in other forms of autoimmune/ inflammatory arthritis, such as RA, to prevent or limit bone erosion and inflammatory bone loss.

Fc Gamma Receptors as Regulators of Bone Destruction in Inflammatory Arthritis

“…These indicate that lupus autoantibodies may also play a protective role in bone destruction in inflammatory arthritis. Recently, our research results ( 26 ) demonstrated that joint-deposited lupus IgG induced arthritis without bone erosion by intraarticular injection of lupus IgG in mice. Monocytes/macrophages and their product TNFα are required for the development of lupus IgG-induced arthritis.…”

“…Our study showed that lupus IgG induced synovial inflammation but inhibited RANKL-induced osteoclastogenesis. The suppressive effect is mediated by the competitive occupation of FcγRI on monocytes/macrophages ( 26 ).…”

“…Our recent study demonstrated that joint-deposited lupus IgG triggered arthritis without bone erosion in mice and lupus IgG inhibited osteoclastogenesis induced by receptor activator of nuclear factor kappa-B ligand (RANKL). FcγRI exerted an inhibitory effect of lupus IgG on RANKL-induced osteoclastogenesis ( 26 ). Our study suggests that FcγR could function as critical regulators of inflammatory arthritis.…”

Don’t Miss Lupus

“…Differential diagnoses would include rheumatoid arthritis, gout, or psoriatic arthritis. Rheumatoid arthritis, psoriatic arthritis, scleroderma, sarcoid and gout are all destructive arthritic diseases [6].…”

The Potential Role of RP105 in Regulation of Inflammation and Osteoclastogenesis During Inflammatory Diseases

“…Bacterial inflammatory diseases such as periodontitis ( Blasco-Baque et al, 2017 ; Gu and Han, 2020 ) and osteomyelitis ( Taubman et al, 2005 ), multiple myeloma ( Westhrin et al, 2020 ), and metabolic diseases like diabetes mellitus ( Watanabe et al, 2013 ) result in hyperactive osteoclastogenesis and progress into severe osteolytic bone diseases. Some autoimmune diseases such as systemic lupus erythematosus (SLE) ( Qiao et al, 2020 ) and osteosarcoma ( Endo-Munoz et al, 2010 ) induce the development of hyperostosis or arthritis as bone destruction is hampered in such cases. Recently, numerous studies have demonstrated that radioprotective 105 kDa (RP105 or CD180) and its ligand, myeloid differentiation protein 1 (MD1) are involved in inflammatory disease-induced osteoclastogenesis and bone loss.…”