CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages

Okada, H.; Kajiya, Hiroshi; Omata, Yasunori; Matsumoto, Takumi; Sato, Yuiko; Kobayashi, Tami; Kaneko, Yosuke; Nakamura, Shinya; Koyama, Takuma; Sudo, Shunichi; Shin, Masashi; Okamoto, Fujio; Watanabe, Hironosuke; Tachibana, Naohiro; Hirose, Jun; Saito, Taku; Takai, Toshiyuki; Matsumoto, Morio; Nakamura, Masaya; Okabe, Koji; Miyamoto, Takeshi; Tanaka, Sakae

doi:10.1002/jbmr.3754

Cited by 20 publications

(23 citation statements)

References 32 publications

(62 reference statements)

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“…Unlike TNFis that primarily inhibit bone resorption [5], abatacept has shown a beneficial effect in both bone resorption and formation in vitro and animal studies [25,26]. In line with this, abatacept treatment was associated with a greater increase in BMD at femoral neck compared with other bDMARDs, mainly TNFis, in a prospective observational study [7].…”

Section: Discussionmentioning

confidence: 78%

Comparative risk of osteoporotic fracture among patients with rheumatoid arthritis receiving TNF inhibitors versus other biologics: a cohort study

Shin

Park

Dong³

et al. 2020

Osteoporos Int

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In this population-based cohort study on comparative osteoporotic fracture risks between different biologic diseasemodifying drugs among patients with rheumatoid arthritis (RA), we did not find a significant difference in the risk of osteoporotic fractures between RA patients receiving TNF inhibitors versus abatacept or tocilizumab. Introduction We aimed to investigate the comparative risk of osteoporotic fractures between rheumatoid arthritis (RA) patients who initiated TNF inhibitors (TNFis) versus abatacept or tocilizumab. Methods Using the Korea National Health Insurance Service datasets from 2002 to 2016, RA patients who initiated TNFis, abatacept, or tocilizumab were identified. The primary outcome was a composite end point of non-vertebral fractures and hospitalized vertebral fractures; secondary outcomes were two components of the primary outcome and fractures occurring at the humerus/forearm. Propensity score (PS) matching with a variable ratio up to 10 TNFi initiators per 1 comparator drug initiator was used to adjust for > 50 baseline confounders. We estimated hazard ratios (HRs) and 95% confidence interval (CI) of fractures comparing TNFi initiators to abatacept and to tocilizumab by Cox proportional hazard models stratified by a matching ratio. Results After PS-matching, 2307 TNFi initiators PS-matched on 588 abatacept initiators, and 2462 TNFi initiators on 640 tocilizumab initiators were included. A total of 77 fractures occurred during a mean follow-up of 454 days among TNFi and abatacept initiators and 83 fractures during 461 days among TNFi and tocilizumab initiators. The PS-matched HR (95% CI

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Section: Discussionmentioning

confidence: 78%

Comparative risk of osteoporotic fracture among patients with rheumatoid arthritis receiving TNF inhibitors versus other biologics: a cohort study

Shin

Park

Dong³

et al. 2020

Osteoporos Int

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“…Mechanistically, Okada and colleagues showed abatacept to inhibit osteoclast differentiation, reduce the expression of nuclear factor of activated T cells c 1(NFATc1), and suppress calcium oscillations in bone marrow-derived macrophages in vitro in an FcyR-dependent manner [264]. In fibroblast-like synoviocytes, abatacept treatment reduced levels of MMP1, MMP3, and MMP15 by 50%-60%, while also inhibiting cell migration in a MAPK-dependent way [265].…”

Section: Inhibitors Of Co-stimulationmentioning

confidence: 99%

Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

Lin

Anzaghe

Schülke

2020

Cells

577

376

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Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally. It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion. While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease. Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage. The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules). While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs. This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs.

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“…In addition, Ca oscillations have not been well examined in the early phase of osteoclast differentiation, because Ca 2+ signaling is considered weak in the immature phase. However, even in BMMs or osteoclast precursor cells, spontaneous Ca oscillations can be observed [21]. The Ca oscillation changes during the time course of osteoclast differentiation from BMMs to mature osteoclasts should be discussed in detail.…”

Section: Ca Oscillation Alterations According To the Differentiation Time Coursementioning

confidence: 99%

“…Our group showed that a rheumatic drug, cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig, inhibits osteoclastogenesis by interfering with Ca 2+ signaling via FcRγ, representing the first report of a cofactor that affects costimulatory signals during osteoclast differentiation [21]. Osteoclastogenesis may be finely-tuned via FcRγ with immunoglobulins and related cofactors according to immunological situations.…”

Section: Fcrγmentioning

confidence: 99%

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Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption

Okada

Okabe

Tanaka

2020

IJMS

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Calcium (Ca2+) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclastogenesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca2+ storage. Ryanodine receptor, inositol trisphosphate receptor, and sarco/endoplasmic reticulum Ca2+ ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains to be examined.

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CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages

Cited by 20 publications

References 32 publications

Comparative risk of osteoporotic fracture among patients with rheumatoid arthritis receiving TNF inhibitors versus other biologics: a cohort study

Comparative risk of osteoporotic fracture among patients with rheumatoid arthritis receiving TNF inhibitors versus other biologics: a cohort study

Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption

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