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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 κB 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.

Key Points

  • A hallmark of rheumatoid arthritis (RA) pathogenesis is an imbalance of the osteoblast–osteoclast axis, which is driven by inflammatory processes

  • Current treatments for RA target synovitis, but do not adequately target bone repair

  • The receptor activator of nuclear factor κB ligand (RANKL) pathway is a key driver of osteoclastogenesis, whilst the Wnt and bone morphogenetic protein pathways drive osteoblastogenesis

  • Dickkopf1 and sclerostin have been shown to act as endogenous inhibitors of the Wnt and bone morphogenetic protein axes

  • Targeting RANKL, Dickkopf1 and scelerostin might have clinical benefit in reducing bone destruction and enhancing repair of erosions in RA

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Figure 1: Bone homeostasis in healthy and RA-affected joints.
Figure 2: Osteoblast differentiation pathways.

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Correspondence to Yongwon Choi.

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Y. Choi declares no competing interests. J. Arron and M. Townsend are employees of Genentech.

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Choi, Y., Arron, J. & Townsend, M. Promising bone-related therapeutic targets for rheumatoid arthritis. Nat Rev Rheumatol 5, 543–548 (2009). https://doi.org/10.1038/nrrheum.2009.175

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