How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by autoimmunity that triggers joint inflammation and tissue destruction. Traditional concepts of RA pathogenesis have strongly been focused on inflammation. However, more recent evidence suggests that autoimmunity per se modulates the disease and in particular bone destruction during the course of RA. RA-associated bone loss is caused by increased osteoclast differentiation and activity leading to rapid bone resorption. Autoimmunity in RA is based on autoantibodies such as rheumatoid factor (RF) and autoantibodies against citrullinated proteins (ACPA). These autoantibodies exert effector functions on immune cells and on bone resorbing osteoclasts, thereby facilitating bone loss. This review summarizes potential pathways involved in increased destruction of bone tissue in RA, particularly focusing on the direct and indirect actions of autoantibodies on osteoclast generation and function.

Keywords: autoantibodies against citrullinated proteins (ACPA); cytokines; osteoclasts; rheumatoid arthritis; rheumatoid factor (RF).

Figure 1

Overview of signaling pathways of (A) Fcγ receptors (FcγRs) on immune cells and (B) co-stimulatory molecules involved in osteoclastogenesis. (A) Crosslinking of activating FcγR (here FcγRIIIA) results in Syk activation starting various signaling pathways that lead to immune cell activation and effector functions like phagocytosis or cytokine production. The distinct signaling pathways have been reviewed in detail in Nimmerjahn and Ravetch (40), Rosales (42). (B) Binding of RANKL to RANK leads to the activation of TRAF6, NFκB, and several MAP kinases resulting in the activation of NFATc1, the master transcription factor for pro-osteoclastogenic genes. For a stable NFATc1 activation, costimulatory signals provided by several receptors associated to the accessory molecules DAP12 or FcRγ, like TREM-2 or OSCAR are needed [reviewed in detail in Humphrey and Nakamura (43)]. These receptors lead to Syk activation with subsequent calcium influx enhancing NFATc1 activation. In a similar way, binding of immune complexes to FcγR initiates co-stimulatory signals, thereby enhancing osteoclastogenesis. BTK, Bruton's tyrosin kinase; DAP12, DNAX activation protein of 12kDa; FcRγ, Fc receptor gamma chain; IC, immune complex; MAPKs, mitogen-activated protein kinases; NFATc1, nuclear factor of activated T cells cytoplasmic 1; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; OSCAR, Osteoclast-associated immunoglobulin-like receptor; PI3K, phosphatidylinositol-3 kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PLCγ, phospholipase Cγ; SHIP, SH2 domain-containing inositol 5'-phosphatase; Syk, spleen tyrosine kinase; Sos, son of Sevenless; TRAF6, TNF receptor associated factor 6; TREM-2, triggering receptor expressed on myeloid cells 2.

Figure 2

Schematic representations of osteoclast differentiation regulated by ACPA or RF antibodies induced cytokines produced by the monocytic lineages. The cytokines, like TNFa, IL1b, IL6, and IL8 are produced by monocyte lineage challenge with ACPA or RF autoantibodies. All these cytokines are directly able to enhance osteoclast formation. Moreover, they can also regulate stromal cells to secrete RANKL, which in turn will induce osteoclast differentiation. It is also well-known that ACPA can influence IL8 secretion by osteoclasts them-selves which will enhance osteoclastogenesis in an autocrine manner.

Figure 3

IgG glycosylation. IgG contains a conserved glycosylation site at the asparagine (Asn)²⁹⁷ in the CH2 domain of the heavy chain. The Fc glycan (depicted in petrol) consists of a conserved heptamer (shaded in blue) that can be extended by various additional sugar residues. Here we show a fully processed glycan containing all sugar residues possible. In addition to the Fc glycan, some IgG molecules contain a glycosylation site in the Fab region (depicted in light petrol) that occurs stochastically due to the introduction of a new glycosylation site during somatic hypermutation. Asn, asparagine; Gal, galactose; GlcNAc, N-acetylglucosamine; Fuc, fucose; Man, mannose; Sial, sialic acid.