Mechanisms of joint destruction in rheumatoid arthritis — immune cell–fibroblast–bone interactions

• Published in: Nature reviews. Rheumatology Vol. 18; no. 7; pp. 415 - 429
• Main Authors: Komatsu, Noriko, Takayanagi, Hiroshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2022; Nature Publishing Group
• Subjects: 692/4023/1670/498; 692/4023/1671/63; 692/4023/808; Bone growth; Bone loss; Bone resorption; Cartilage; Fibroblasts; Immune system; Immunoregulation; Inflammation; Joint diseases; Lymphocytes T; Macrophages; Medicine; Medicine & Public Health; Osteoclastogenesis; Osteoclasts; Osteogenesis; Osteoporosis; Review Article; Rheumatoid arthritis; Rheumatology; Therapeutic targets; TRANCE protein
• ISSN: 1759-4790; 1759-4804
• DOI: 10.1038/s41584-022-00793-5

Rheumatoid arthritis (RA) is characterized by inflammation and destruction of bone and cartilage in affected joints. Autoimmune responses lead to increased osteoclastic bone resorption and impaired osteoblastic bone formation, the imbalance of which underlies bone loss in RA, which includes bone erosion, periarticular bone loss and systemic osteoporosis. The crucial role of osteoclasts in bone erosion has been demonstrated in basic studies as well as by the clinical efficacy of antibodies targeting RANKL, an important mediator of osteoclastogenesis. Synovial fibroblasts contribute to joint damage by stimulating both pro-inflammatory and tissue-destructive pathways. New technologies, such as single-cell RNA sequencing, have revealed the heterogeneity of synovial fibroblasts and of immune cells including T cells and macrophages. To understand the mechanisms of bone damage in RA, it is important to clarify how the immune system promotes the tissue-destructive properties of synovial fibroblasts and influences bone cells. The interaction between immune cells and fibroblasts underlies the imbalance between regulatory T cells and T helper 17 cells, which in turn exacerbates not only inflammation but also bone destruction, mainly by promoting RANKL expression on synovial fibroblasts. An improved understanding of the immune mechanisms underlying joint damage and the interplay between the immune system, synovial fibroblasts and bone will contribute to the identification of novel therapeutic targets in RA.
In this Review, the authors provide an overview of the mechanisms contributing to joint damage in rheumatoid arthritis, particularly the interactions among immune cells, fibroblasts and bone, and discuss how this knowledge could inform the development of novel therapies.
Key points
T helper 17 (T
H
17) cells and autoantibodies promote inflammation and tissue destruction in rheumatoid arthritis (RA) by activating other immune cells and synovial fibroblasts, leading to synovitis, bone erosion and cartilage damage.
Synovial fibroblasts in RA comprise pro-inflammatory and tissue-destructive subsets, the latter of which express RANKL and matrix metalloproteinases that are involved in osteoclastic bone resorption and cartilage degradation, respectively.
Bone lesions in RA are classified as bone erosion, periarticular bone loss and systemic osteoporosis, which are induced by distinct mechanisms.
The integration of data from single-cell RNA sequencing and biological studies provides a detailed depiction of the interplay among immune cells, fibroblasts and bone in RA pathogenesis.
Therapeutic strategies to modulate pathogenic synovial fibroblasts and to achieve a balance between regulatory T cells and T
H
17 cells and/or between bone resorption and repair will help achieve structural remission.