Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment

Schett, Georg; Gravallese, Ellen

doi:10.1038/nrrheum.2012.153

Cited by 947Rheumatoid Arthritis Research and TherapiesBone Metabolism and DiseasesOsteoarthritis Treatment and Mechanisms

Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment

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Schett, Georg, Gravallese, Ellen·2012·Nature Reviews Rheumatology

DOI 10.1038/nrrheum.2012.153PMC PMC4096779

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Abstract

Bone erosion is a central feature of rheumatoid arthritis and is associated with disease severity and poor functional outcome. Erosion of periarticular cortical bone, the typical feature observed on plain radiographs in patients with rheumatoid arthritis, results from excessive local bone resorption and inadequate bone formation. The main triggers of articular bone erosion are synovitis, including the production of proinflammatory cytokines and receptor activator of nuclear factor κB ligand (RANKL), as well as antibodies directed against citrullinated proteins. Indeed, both cytokines and autoantibodies stimulate the differentiation of bone-resorbing osteoclasts, thereby stimulating local bone resorption. Although current antirheumatic therapy inhibits both bone erosion and inflammation, repair of existing bone lesions, albeit physiologically feasible, occurs rarely. Lack of repair is due, at least in part, to active suppression of bone formation by proinflammatory cytokines. This Review summarizes the substantial progress that has been made in understanding the pathophysiology of bone erosions and discusses the improvements in the diagnosis, monitoring and treatment of such lesions.

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TNF-α can indirectly increase RANKL expression and affect osteoclast differentiation by activating osteoblasts, B cells, and T cells.
“TNF-α can also indirectly increase RANKL expression and affect osteoclast differentiation by activating osteoblasts, B cells, and T cells [88].”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [88]
The 'Pathways for osteoclast differentiation' section (page unavailable) says TNF stimulates receptors on osteoclast precursors that facilitate differentiation, and identifies RANKL as essential to that process. It does not say TNF increases RANKL by activating osteoblasts, B cells, or T cells; the 'Proinflammatory cytokines in bone erosion' section instead identifies IL-17 as an inducer of RANKL on osteoblasts. (LLM, conf=0.84)
Experimental — accuracy not yet measured
RANKL-dependent pathways activated by pro-inflammatory cytokines can induce osteoclast formation and enhance osteoclast activity.
“RANKL-dependent pathways activated by pro-inflammatory cytokines can induce osteoclast formation, therefore, enhancing osteoclast activity [87, 88].”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [88]

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CTLA-4 directly inhibits osteoclast formation
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Periarticular bone structure in rheumatoid arthritis patients and healthy individuals assessed by high‐resolution computed tomography
Stach, C. M., Bäuerle, M., Englbrecht, M., Krönke, G., Engelke, K., Manger, B., & Schett, G. A. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27252 · Cited by 188 · see citing works
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Magnetic resonance imaging of wrist and finger joints in healthy subjects occasionally shows changes resembling erosions and synovitis as seen in rheumatoid arthritis
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Changes in hand and generalised bone mineral density in patients with recent-onset rheumatoid arthritis
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No overall progression and occasional repair of erosions despite persistent inflammation in adalimumab-treated rheumatoid arthritis patients: results from a longitudinal comparative MRI, ultrasonography, CT and radiography study
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Inhibition of RANK Expression and Osteoclastogenesis by TLRs and IFN-γ in Human Osteoclast Precursors
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Association of early radiographic damage with impaired physical function in rheumatoid arthritis: A ten‐year, longitudinal observational study in 238 patients
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Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway
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Osteoimmunology and osteoporosis
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Inflammation is preceded by tumor necrosis factor‐dependent infiltration of mesenchymal cells in experimental arthritis
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A Novel Role of IL-15 in the Development of Osteoclasts: Inability to Replace Its Activity with IL-2
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The multiple faces of autoimmune-mediated bone loss
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Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis.
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A comparative study of periarticular bone lesions in rheumatoid arthritis and psoriatic arthritis
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The Pattern of Bone Erosion in the Hand and Wrist in Rheumatoid Arthritis
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Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion
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Rheumatoid arthritis bone erosion volumes on CT and MRI: reliability and correlations with erosion scores on CT, MRI and radiography
Døhn, U. M., Ejbjerg, B., Hasselquist, M., Narvestad, E., Court‐Payen, M., Szkudlarek, M., Møller, J. M., Thomsen, H., & Østergaard, M. (2007) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2007.072520 · Cited by 123 · see citing works
Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation
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How antirheumatic drugs protect joints from damage in rheumatoid arthritis.
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Radiological damage in patients with rheumatoid arthritis on sustained remission
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Role of metacarpophalangeal joint anatomic factors in the distribution of synovitis and bone erosion in early rheumatoid arthritis
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Cortical hand bone loss after 1 year in early rheumatoid arthritis predicts radiographic hand joint damage at 5-year and 10-year follow-up
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A detailed comparative study of high‐resolution ultrasound and micro–computed tomography for detection of arthritic bone erosions
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Interleukin-6 receptor blockade induces limited repair of bone erosions in rheumatoid arthritis: a micro CT study
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IL-33 Shifts the Balance from Osteoclast to Alternatively Activated Macrophage Differentiation and Protects from TNF-α–Mediated Bone Loss
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Induction of osteoclast‐associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis
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Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis
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IL-23 Inhibits Osteoclastogenesis Indirectly through Lymphocytes and Is Required for the Maintenance of Bone Mass in Mice
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From bone biology to clinical outcome: state of the art and future perspectives
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Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1 year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure
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Hand cortical bone mass and its associations with radiographic joint damage and fractures in 50–70 year old female patients with rheumatoid arthritis: cross sectional Oslo-Truro-Amsterdam (OSTRA) collaborative study
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Microanatomic studies to define predictive factors for the topography of periarticular erosion formation in inflammatory arthritis
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The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis
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Increase in expression of receptor activator of nuclear factor κB at sites of bone erosion correlates with progression of inflammation in evolving collagen‐induced arthritis
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Osteoclasts—the innate immune cells of the bone
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Repair of erosions occurs almost exclusively in damaged joints without swelling
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The orally‐active and selective c‐Fms tyrosine kinase inhibitor Ki20227 inhibits disease progression in a collagen‐induced arthritis mouse model
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Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis
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The erosive front: a topographic study of the junction between the pannus and the subchondral plate in the macerated rheumatoid metacarpal head.
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Analysis of the kinetics of osteoclastogenesis in arthritic rats
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Detection of cellular microchimerism of male or female origin in systemic sclerosis patients by polymerase chain reaction analysis of HLA–Cw antigens
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Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance
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Paucity of radiographic progression in rheumatoid arthritis treated with methotrexate as the first disease modifying antirheumatic drug.
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Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study
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Nuclear antigen histone H1 is primarily involved in lupus erythematosus cell formation
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Reduced trabecular bone mineral density and cortical thickness accompanied by increased outer bone circumference in metacarpal bone of rheumatoid arthritis patients: a cross-sectional study
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Die feineren Veränderungen des Gelenkknorpels bei fungöser Synovitis und Caries der Gelenkenden
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Disease activity and severity in early inflammatory arthritis predict hand cortical bone loss
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Rheumatology and the health of the workforce
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Effect of Rheumatoid Arthritis on Volumetric Bone Mineral Density and Bone Geometry, Assessed by Peripheral Quantitative Computed Tomography in Postmenopausal Women Treated with Bisphosphonates
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OSCAR, a key co-stimulation molecule for osteoclasts, is induced in patients with rheumatoid arthritis
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Genetic variants in IL-15 associate with progression of joint destruction in rheumatoid arthritis, a multi cohort study
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The effects of interferon-beta treatment of synovial inflammation and expression of metalloproteinases in patients with rheumatoid arthritis
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The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis
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[105]Sato K TH17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction J. Exp. Med 2006 203 2673 2682 17088434 PMC2118166

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Authors: Schett, G., & Gravallese, E.
Affiliations: Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
University of Massachusetts Chan Medical School (US)
Corresponding author: Schett, Georg
ORCID: Schett, Georg
Gravallese, Ellen
Venue: Nature Reviews Rheumatology
Publisher: Springer Science and Business Media LLC
Published: 2012-09-25
Volume: 8
Issue: 11
Pages: 656-664
ISSN: 1759-4790 (ISSN-L)
1759-4804
DOI: 10.1038/nrrheum.2012.153
PMC: PMC4096779
OpenAlex: W2032362610
Cited by: 947
References: 124
Citations by year: 2026: 72 · 2025: 72 · 2024: 89 · 2023: 75 · 2022: 82 · 2021: 89 · 2020: 80 · 2019: 75 · 2018: 73 · 2017: 74 · 2016: 53 · 2015: 52 · 2014: 35 · 2013: 26
FWCI: 5.39
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Rheumatology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
Funders: American College of Rheumatology Research and Education Foundation
Rheumatology Research Foundation
European Commission
Deutsche Forschungsgemeinschaft
Bundesministerium für Bildung und Forschung
National Institutes of Health (5r01ar055952-05)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR055952)
Topics: Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords: bone erosion, rheumatoid arthritis, bone resorption, osteoclasts, synovitis, inflammatory cytokines, RANKL, anti-citrullinated protein antibodies, bone formation, bone regeneration, radiographic erosions, antirheumatic therapy
MeSH terms: Animals, Arthritis, Rheumatoid, Bone Resorption, Cell Differentiation, Humans, Osteoclasts, Cytokines

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