Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis

Shimizu, Satoru; Shiozawa, Shunichi; Shiozawa, Kazuko; Imura, Satoru; Fujita, Takeshi

doi:10.1002/art.1780280105

Cited by 140 publications

(66 citation statements)

References 28 publications

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“…Histologic analysis has demonstrated an increased level of osteoclastic bone resorption at the bone-pannus interface in RA joints (26). Previous studies have shown that both peripheral blood and synovial monocyte/macrophages have the ability to function as osteoclast precursors and develop osteoclastic activity when cocultured with either CD14-negative synovial cells or FLS in the presence of M-CSF (4,7-10).…”

Section: Discussionmentioning

confidence: 99%

Development of an ex vivo cellular model of rheumatoid arthritis: Critical role of cd14‐positive monocyte/macrophages in the development of pannus tissue

Nozaki¹,

Takahashi²,

Ishii³

et al. 2007

Arthritis & Rheumatism

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Objective. To establish an ex vivo cellular model of pannus, the aberrant overgrowth of human synovial tissue (ST).Methods. Inflammatory cells that infiltrated pannus tissue from patients with rheumatoid arthritis (RA) were collected without enzyme digestion, and designated as ST-derived inflammatory cells. Single-cell suspensions of ST-derived inflammatory cells were cultured in medium alone. Levels of cytokines produced in culture supernatants were measured using enzyme-linked immunosorbent assay kits. ST-derived inflammatory cells were transferred into the joints of immunodeficient mice to explore whether these cells could develop pannus. CD14 and CD2 cells were depleted by negative selection.Results Conclusion. These findings suggest that overgrowth of inflammatory cells from human rheumatoid synovium simulates the development of pannus. This may prove informative in the screening of potential antirheumatic drugs.

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Section: Discussionmentioning

confidence: 99%

Development of an ex vivo cellular model of rheumatoid arthritis: Critical role of cd14‐positive monocyte/macrophages in the development of pannus tissue

Nozaki¹,

Takahashi²,

Ishii³

et al. 2007

Arthritis & Rheumatism

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“…Furthermore, RA synovial tissue can be considered a suitable microenvironment for osteoclastogenesis, since synovial T cells and fibroblasts express RANKL in situ (16,17), potentially serving as nursing cells (34), and a large number of cells of the monocyte/ macrophage lineage, possibly serving as osteoclast progenitors, accumulate in the inflammatory lesions of RA (35). In fact, both osteoclast progenitors and mature osteoclasts have been described as being present at the site of bone erosions in human RA (12,13,36). Nevertheless, linking the mere presence of osteoclasts at the site of bone erosion to an essential role in inducing these lesions appeared far more difficult.…”

Section: Tablementioning

confidence: 99%

Osteoclasts are essential for TNF-α–mediated joint destruction

Redlich¹,

Hayer²,

Ricci³

et al. 2002

J. Clin. Invest.

270

171

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The detailed cellular and molecular mechanisms leading to joint destruction in rheumatoid arthritis, a disease driven by proinflammatory cytokines, are still unknown. To address the question of whether osteoclasts play a pivotal role in this process, transgenic mice that express human TNF (hTNFtg) and that develop a severe and destructive arthritis were crossed with osteopetrotic, c-fos–deficient mice (c-fos–/–) completely lacking osteoclasts. The resulting mutant mice (c-fos–/–hTNFtg) developed a TNF-dependent arthritis in the absence of osteoclasts. All clinical features of arthritis, such as paw swelling and reduction of grip strength, progressed equally in both groups. Histological evaluation of joint sections revealed no difference in the extent of synovial inflammation, its cellular composition (except for the lack of osteoclasts), and the expression of matrix metalloprotein-ase-3 (MMP-3) and MMP-13. In addition, cartilage damage, proteoglycan loss, and MMP-3, -9, and -13 expression in chondrocytes were similar in hTNFtg and c-fos–/–hTNFtg mice. However, despite the presence of severe inflammatory changes, c-fos–/–hTNFtg mice were fully protected against bone destruction. These data reveal that TNF-dependent bone erosion is mediated by osteoclasts and that the absence of osteoclasts alters TNF-mediated arthritis from a destructive to a nondestructive arthritis. Therefore, in addition to the use of anti-inflammatory therapies, osteoclast inhibition could be beneficial for the treatment of rheumatoid arthritis

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“…Bone destruction is mediated by the multinucleated giant cells, osteoclasts. [1][2][3] Abundant expression of inflammatory cytokines upregulates osteoclastogenesis within the inflamed regions. Methotrexate (MTX), a monomethylated aminopterin, is widely used and is one of the most effective therapeutics for the treatment of RA.…”

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confidence: 99%

Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis

Teramachi

Kukita

et al. 2011

Laboratory Investigation

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Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-kB ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A 2b adenosine receptor (A 2b AR), but not by caffeine, an antagonist for A 1 , A 2a , A 3 AR (A 1 AR, A 2a AR, and A 3 AR), which suggests that adenosine acts through A 2b AR. Immunohistochemical studies showed abundant expression of A 2b AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A 2b AR system may explain MTX resistance in RA.

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Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis

Cited by 140 publications

References 28 publications

Development of an ex vivo cellular model of rheumatoid arthritis: Critical role of cd14‐positive monocyte/macrophages in the development of pannus tissue

Development of an ex vivo cellular model of rheumatoid arthritis: Critical role of cd14‐positive monocyte/macrophages in the development of pannus tissue

Osteoclasts are essential for TNF-α–mediated joint destruction

Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis

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