Osteoimmunology: The Crosstalk between T Cells, B Cells, and Osteoclasts in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is an ongoing inflammatory condition that affects the joints and can lead to severe damage to cartilage and bones, resulting in significant disability. This condition occurs when the immune system becomes overactive, causing osteoclasts, cells responsible for breaking down bone, to become more active than necessary, leading to bone breakdown. RA disrupts the equilibrium between osteoclasts and osteoblasts, resulting in serious complications such as localized bone erosion, weakened bones surrounding the joints, and even widespread osteoporosis. Antibodies against the receptor activator of nuclear factor-κB ligand (RANKL), a crucial stimulator of osteoclast differentiation, have shown great effectiveness both in laboratory settings and actual patient cases. Researchers are increasingly focusing on osteoclasts as significant contributors to bone erosion in RA. Given that RA involves an overactive immune system, T cells and B cells play a pivotal role by intensifying the immune response. The imbalance between Th17 cells and Treg cells, premature aging of T cells, and excessive production of antibodies by B cells not only exacerbate inflammation but also accelerate bone destruction. Understanding the connection between the immune system and osteoclasts is crucial for comprehending the impact of RA on bone health. By delving into the immune mechanisms that lead to joint damage, exploring the interactions between the immune system and osteoclasts, and investigating new biomarkers for RA, we can significantly improve early diagnosis, treatment, and prognosis of this condition.

Keywords: B cell; T cell; osteoclasts; osteoimmunology; rheumatoid arthritis.

Figure 1

T cells, B cells, and osteoclasts in the immune machinery in RA. This figure illustrates the role of T cells, B cells, and osteoclasts in the immune machinery of RA. Activated T cells and B cells secrete pro-inflammatory factors such as IL-1β, IL-6, and TNF-α, among others. In the inflammatory microenvironment of RA joints, these cytokines promote the differentiation of FLS into tissue-damaging FLS and the release of RANKL—the primary factor promoting the generation of osteoclasts. Furthermore, T cells and B cells also contribute to the secretion of RANKL. Upon the junction of RANKL with RANK on the osteoclast precursors, a cascade of pathways will induce the differentiation of osteoclasts, leading to their maturation and ultimately contributing to bone erosion.

Figure 2

Positive and negative regulation of osteoclast differentiation. Initially, osteoclast precursors are located in the periosteal vasculature due to high concentrations of S1P. Subsequently, they migrate into the bone cavity in response to varying S1P concentrations and chemokines such as CXCL12 and CX3CL1. Upon reaching their destination, the osteoclast precursors differentiate and mature under the influence of pro-osteoclast genesis factors, including RANKL. (A) RANKL binds to RANK receptors expressed by osteoclast precursors, forming complexes with TRAF6, TAB1, and TAB2. This interaction activates TAK1 and triggers MAPKs and NF-κB cascade signaling. Consequently, activated c-Fos induces the expression of NFATc1. NFATc1 then binds to AP-1, CREB, PU.1, and other targets, including its own promoter, leading to the transcription of various osteoclast-specific genes (such as Ctsk, MMP9, etc.), creating a self-induced closed loop. NFATc1 also induces the transcriptional repressor BLIMP1, which inhibits the generation of anti-osteoclast genes like Irf8, Bcl6, and Mafb. CaMKIV-CREB signaling, PPARγ, PGC1β, and C/EBPα signaling can synergize with NF-κB signaling to induce c-Fos and consequently promote NFATc1 expression. Additionally, SEMA6D enhances osteoclast formation by activating ITAM signaling, followed by CaMKIV-CREB signaling, through the formation of the Plexin-A1-TREM2-dap12 complex. (B) OPG competes with RANKL for binding to RANK, thereby blocking the signals triggered by RANKL in the positive regulatory pathway described above. Notably, Irf8 and Bcl6 directly interact with and inhibit the expression of NFATc1. Furthermore, other transcription factors including ATF4, LRF, and Jdp2 negatively regulate NFATc1. Pax5 inhibits BLIMP1 expression, FcγRIIB inhibits ITAM signaling, and the SEMA3A-nrp1 axis restricts ITAM signaling by segregating Plexin-A1 from TREM2. Additionally, miR-34a acts as a negative regulator of osteoclast differentiation by inhibiting NF-κB signaling. Another receptor for RANKL, lGR4, functions similarly to OPG in blocking RANKL signals.

Figure 3

The interaction between T cells, B cells, and osteoclasts in RA. Within the joint microenvironment of RA, T cells, B cells, and interact in a complex and interconnected manner. Cytokines released by T cells and B cells, such as RANKL, IL-17, TNF-α, and IL-1β, promote osteoclast formation, while cytokines like IL-10 and TGF-β act to inhibit this process. Disruption of these delicate balances can lead to the establishment of a self-sustaining inflammatory environment, triggering abnormal activation of osteoclasts, excessive secretion of bone-degrading enzymes, and ultimately severe bone damage.