Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Apr 23:8:F1000 Faculty Rev-533.
doi: 10.12688/f1000research.17296.1. eCollection 2019.

RANKL is a therapeutic target of bone destruction in rheumatoid arthritis

Sakae Tanaka  1
Affiliations
Review

RANKL is a therapeutic target of bone destruction in rheumatoid arthritis

Sakae Tanaka. F1000Res. .

Abstract

Although remarkable advances have been made in the treatment of rheumatoid arthritis (RA), novel therapeutic options with different mechanisms of action and fewer side effects have been expected. Recent studies have demonstrated that bone-resorbing osteoclasts are critically involved in the bone destruction associated with RA. Denosumab, a human antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), efficiently suppressed the progression of bone erosion in patients with RA by suppressing osteoclast differentiation and activation in several clinical studies, although it had no effect on inflammation or cartilage destruction. Denosumab, in combination with anti-rheumatic drugs, is considered a pivotal therapeutic option for the prevention of bone destruction in RA.

Keywords: Denosumab; RANKL; osteoclast; rheumatoid arthritis.

PubMed Disclaimer

Conflict of interest statement

Competing interests: ST received consulting or speaking fees or honoraria (or a combination of these) from Asahikasei Pharma Co., Daiichi-Sankyo Co. Ltd., Mitsubishi-Tanabe Pharma Co., and Teijin Pharma Ltd. and research grants from Astellas Pharma Inc., Asahikasei Pharma Co., AYUMI Pharmaceutical Co., Chugai Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., Stryker Japan K.K., Taisho Toyama Pharmaceutical Co. Ltd., and Teijin Pharma Ltd.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Bone erosion in rheumatoid arthritis.
The proliferating synovium stimulates osteoclast differentiation, and many osteoclasts are observed at the synovium–bone interface (arrow).
Figure 2.
Figure 2.. Denosumab significantly suppresses the bone erosion score but has no effect on the joint-space narrowing score determined by modified Sharp scores.
( a) Modified Sharp erosion score. ( b) Modified Sharp joint-space narrowing score. CI, confidence interval; Q2M, every 2 months; Q3M, every 3 months; Q6M, every 6 months. Modified from a figure in an article by Takeuchi et al. .
Figure 3.
Figure 3.. Schematic representation of the mechanism for osteoclast development and denosumab action in rheumatoid arthritis.
Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-17 directly or indirectly induce receptor activator of nuclear factor-kappa B ligand (RANKL) expression in synovial fibroblasts or osteoblasts or both. RANKL stimulates osteoclast differentiation from monocyte/macrophage-lineage precursor cells, leading to bone erosion in rheumatoid arthritis. Denosumab specifically binds to RANKL and suppresses osteoclast differentiation.
See this image and copyright information in PMC

References

    1. Firestein GS: Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–61. 10.1038/nature01661 - DOI - PubMed
    1. Schett G: Autoimmunity as a trigger for structural bone damage in rheumatoid arthritis. Mod Rheumatol. 2017;27(2):193–7. 10.1080/14397595.2016.1265907 - DOI - PubMed

    2. F1000 Recommendation

    1. Wassenberg S, Rau R: Radiographic healing with sustained clinical remission in a patient with rheumatoid arthritis receiving methotrexate monotherapy. Arthritis Rheum. 2002;46(10):2804–7. 10.1002/art.10568 - DOI - PubMed
    1. Tanaka S, Nakamura K, Takahasi N, et al. : Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunol Rev. 2005;208:30–49. 10.1111/j.0105-2896.2005.00327.x - DOI - PubMed
    1. Bromley M, Woolley DE: Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint. Arthritis Rheum. 1984;27(9):968–75. 10.1002/art.1780270902 - DOI - PubMed