IgG immune complexes directly regulate bone homeostasis

New research published in Nature Communications highlights important links between the adaptive immune system and bone metabolism. The two separate studies, by Negishi-Koga et al. and Harre et al., provide insights into the mechanisms by which IgG immune complexes (ICs) control osteoclastogenesis under physiological conditions and in the context of autoimmune disease.

IgG is known to regulate the immune response through binding to activating or inhibitory Fcγ receptors (FcγRs), but the role of the IgG–FcγR system in bone homeostasis is less well understood. “We and others previously showed that FcRγ, the common gamma chain for all FcγRs, is involved in osteoclastogenesis but it was unclear how, because FcRγ knockout mice had a normal bone phenotype,” according to Hiroshi Takayanagi, corresponding author on the paper by Negishi-Koga et al. “We tried to address whether and how FcγRs and their ligand, IgG immune complexes, regulate osteoclasts directly.”

The investigators focused on the two FcγRs predominantly expressed in mouse osteoclast precursor cells: the positive (activating) receptor FcγRIII (encoded by Fcgr3 in mice) and the negative (inhibitory) receptor FcγRIIB (encoded by Fcgr2b). Surprisingly, Fcgr3^−/− mice had an osteoporotic phenotype, attributable to increased osteoclastic bone resorption. Negishi-Koga et al. determined that, under physiological conditions, FcγRIII limits the availability of the FcRγ subunit for other FcRγ-associated immunoglobulin-like activating receptors, thus negatively regulating the co-stimulatory signal for osteoclastogenesis.

Credit: NPG

The question of how FcγRIII regulates osteoclastogenesis in the presence of IgG ICs prompted them to examine the role of FcγRIIB, which antagonizes FcγRIII signalling in immune cells by binding to IgG₁ with a higher affinity than FcγRIII binding to IgG₁. Fcgr2b^−/− mice also developed an osteoporotic phenotype, but only in association with hypergammaglobulinaemia or after systemic administration of IgG ICs. The investigators deduced that IgG₁ ICs stimulate osteoclastogenesis via FcγRIII when the inhibitory effect of FcγRIIB is downregulated. Furthermore, they showed that IgG₂ ICs stimulate osteoclastogenesis via the activating receptors FcγRI and FcγRIV—to which IgG₂ binds with a higher affinity than to the inhibitory receptor FcγRIIB. Of note, Negishi-Koga et al. also observed that desialylation of IgGs contibutes to osteoclastogenesis in mice in inflammatory conditions.

“IgG immune complexes bind to the FcγRs on osteoclast precursor cells and directly regulate bone resorption,” explains Takayanagi. “The role of antibodies is usually only related to the[ir] immune function, but this is an interesting and rare example of quite a different role.” The findings might also have a bearing on the development of new therapeutic approaches to inflammatory bone disease. As Takayanagi notes, “IgG levels are high in many diseases, and we can understand the mechanism of bone loss—joint erosion and systemic or periarticular osteoporosis—associated with such diseases and think about the future therapy for these situations.”

In a complementary study, Harre et al. highlight the relevance of this mechanism to human osteoclast differentiation and provide an explanation for the association of bone loss with autoimmune diseases. The researchers, led by Georg Schett, showed that desialylation of IgG improves binding to FcγRs and enables more robust activation of preosteoclasts.

Stimulation of human preosteoclasts with desialylated ICs led to accelerated osteoclastogenesis in vitro, in comparison to stimulation with sialylated ICs; similarly, only injection of desialylated ICs stimulated osteoclastogenesis in vivo in C57BL/6 mice. In accordance with these experimental findings, Harre et al. found that the Fc sialylation levels of both nonspecific IgG and anti-citrullinated protein antibodies (ACPA) directly correlated with bone volume in patients with rheumatoid arthritis (RA). Moreover, enzymatic sialylation of human monoclonal ACPA led to a loss of the pro-osteoclastogenic activity of these antibodies. Finally, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc) to increase IgG sialylation were less susceptible to collagen-induced arthritis than were mice treated with water or mannose. In addition, the ManNAc-treated mice were protected from local and systemic bone loss.

Together, the results of these studies clarify the mechanisms by which the immune response influences bone metabolism, and suggest the potential of targeting IgG ICs for the treatment of autoimmune-mediated bone loss.