Promising bone-related therapeutic targets for rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that results in inflammation and structural destruction of the joints. A hallmark of RA pathogenesis is an imbalance of the osteoblast-osteoclast axis driven by inflammatory processes, resulting in elevated bone resorption by osteoclasts. Current therapies used to treat this disease have focused on inhibition of synovitis, but such treatments do not adequately repair damaged bone. A key pathway of osteoclast formation involves the receptor activator of nuclear factor kappaB ligand (RANKL) pathway acting on myeloid progenitor cells. The Wnt pathway has been shown to be important for the differentiation of osteoblasts from mesenchymal lineage precursors, and endogenous Wnt inhibitors, such as Dickkopf1 and sclerostin, might have important roles in osteoclast dysregulation in RA. Inhibition of the RANKL pathway, or blockade of Dickkopf1 and sclerostin, might serve to restore the osteoblast-osteoclast balance and repair bone erosion in RA joints. Such treatments, in combination with anti-inflammatory therapies, could stabilize and repair damaged joints and have the potential to be valuable additions to the armory of RA treatments.

Figure 1. Bone homeostasis in healthy and RA joints

In normal joints, bone formation and bone resorption are maintained by the balanced function of osteoblasts and osteoclasts. The molecular basis of this homeostasis is controlled in part by the opposing actions of Wnt and BMP pathways on osteoblasts and the RANKL pathway on osteoclasts. Under the inflammatory conditions of RA, activity of infiltrating macrophages and CD4⁺ T cells results in expression of proinflammatory cytokines such as TNF that drive osteoclast formation via induction of RANKL in the synovium. In addition, RANKL is expressed on synovial fibroblasts and infiltrating T cells. The resulting osteoclasts, and associated local production of H⁺ ions and cathepsin K, result in increased bone resorption and joint destruction. BMP, bone morphogenetic protein; FLS, fibroblast-like synoviocyte; IL, interleukin; MMPs, matrix metalloproteinases; NO, nitric oxide; RA, rheumatoid arthritis; RANKL, Receptor activator of NF-κB Ligand; TNF, tumor necrosis factor; TRAP, tartrate-resistant acid phosphastase

Figure 2. Osteoblast differentiation pathways

Osteoblast formation from mesenchymal progenitors is controlled by the canonical Wnt–β catenin and the BMP pathways. Engagement of plasma membrane Wnt receptors LRP5 and LRP6 and the coreceptor FZD by Wnt leads to activation of DVL, which blocks a protein complex comprising axin, APC and GSK3. This allows the translocation of β-catenin to the nucleus, where it complexes with TCF/LEF1 and binds DNA. In addition, binding of BMP to its membrane receptor complex activates a signaling cascade involving heteromeric SMAD protein complexes, which translocate to the nucleus and bind DNA. Both of these transcriptional complexes then drive osteoblastogenic gene expression programs. DKK1 and sclerostin are endogenous proteins that inhibit osteoblast differentiation by binding to the LRP receptors and blocking Wnt docking. In addition, sclerostin binds BMPs and so can potentially block this pathway too. APC, adenomatosis polyposis coli; BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; CK1, casein kinase 1; DKK1, Dickkopf1; DVL, human homolog of the Drosophila dishevelled gene; FZD, frizzled; GSK3, glycogen synthase kinase 3; LRP, LDL receptor-related protein; SMAD, TCF/LEF1, T cell factor/lymphoid enhancer binding factor 1.