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Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis.

ABSTRACT: In rheumatoid arthritis (RA), osteoclastic bone resorption causes structural joint damage as well as periarticular and systemic bone loss. Periarticular bone loss is one of the earliest indices of RA, often preceding the onset of clinical symptoms via largely unknown mechanisms. Excessive osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL) expressed by synovial fibroblasts causes joint erosion, whereas the role of RANKL expressed by lymphocytes in various types of bone damage has yet to be elucidated. In the bone marrow of arthritic mice, we found an increase in the number of RANKL-expressing plasma cells, which displayed an ability to induce osteoclastogenesis in vitro. Genetic ablation of RANKL in B-lineage cells resulted in amelioration of periarticular bone loss, but not of articular erosion or systemic bone loss, in autoimmune arthritis. We also show conclusive evidence for the critical contribution of synovial fibroblast RANKL to joint erosion in collagen-induced arthritis on the arthritogenic DBA/1J background. This study highlights the importance of plasma-cell RANKL in periarticular bone loss in arthritis and provides mechanistic insight into the early manifestation of bone lesion induced by autoimmunity.

SUBMITTER: Komatsu N

PROVIDER: S-EPMC7954598 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis.

Komatsu Noriko N Win Stephanie S Yan Minglu M Huynh Nam Cong-Nhat NC Sawa Shinichiro S Tsukasaki Masayuki M Terashima Asuka A Pluemsakunthai Warunee W Kollias George G Nakashima Tomoki T Takayanagi Hiroshi H

The Journal of clinical investigation 20210301 6

In rheumatoid arthritis (RA), osteoclastic bone resorption causes structural joint damage as well as periarticular and systemic bone loss. Periarticular bone loss is one of the earliest indices of RA, often preceding the onset of clinical symptoms via largely unknown mechanisms. Excessive osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL) expressed by synovial fibroblasts causes joint erosion, whereas the role of RANKL expressed by lymphocytes in various types of bone damag ...[more]

PMID: 33720039

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Project description:BackgroundThe types of bone damage in rheumatoid arthritis (RA) include joint erosion, periarticular osteoporosis, and systemic osteoporosis. Janus kinase (JAK) inhibitors ameliorate inflammation and joint erosion in RA, but their effect on the three types of bone loss have not been reportedly explored in depth. We aimed to clarify how JAK inhibitors influence the various types of bone loss in arthritis by modulating osteoclastic bone resorption and/or osteoblastic bone formation.MethodsCollagen-induced arthritis (CIA) mice were treated with a JAK inhibitor after the onset of arthritis. Micro-computed tomography (μCT) and histological analyses (bone morphometric analyses) on the erosive calcaneocuboid joint, periarticular bone (distal femur or proximal tibia), and vertebrae were performed. The effect of four different JAK inhibitors on osteoclastogenesis under various conditions was examined in vitro.ResultsThe JAK inhibitor ameliorated joint erosion, periarticular osteopenia and systemic bone loss. It reduced the osteoclast number in all the three types of bone damage. The JAK inhibitor enhanced osteoblastic bone formation in the calcaneus distal to inflammatory synovium in the calcaneocuboid joints, periarticular region of the tibia and vertebrae, but not the inflamed calcaneocuboid joint. All the JAK inhibitors suppressed osteoclastogenesis in vitro to a similar extent in the presence of osteoblastic cells. Most of the JAK inhibitors abrogated the suppressive effect of Th1 cells on osteoclastogenesis by inhibiting IFN-γ signaling in osteoclast precursor cells, while a JAK inhibitor did not affect this effect due to less ability to inhibit IFN-γ signaling.ConclusionsThe JAK inhibitor suppressed joint erosion mainly by inhibiting osteoclastogenesis, while it ameliorated periarticular osteopenia and systemic bone loss by both inhibiting osteoclastogenesis and promoting osteoblastogenesis. These results indicate that the effect of JAK inhibitors on osteoclastogenesis and osteoblastogenesis depends on the bone damage type and the affected bone area. In vitro studies suggest that while JAK inhibitors inhibit osteoclastic bone resorption, their effects on osteoclastogenesis in inflammatory environments vary depending on the cytokine milieu, JAK selectivity and cytokine signaling specificity. The findings reported here should contribute to the strategic use of antirheumatic drugs against structural damages in RA.

Project description:BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by disrupted bone homeostasis. This study investigated the effect and underlying mechanisms of one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) on osteoclast differentiation and bone loss in RA.MethodsThe expression of MTHFD2 was examined in CD14 + monocytes and murine bone marrow-derived macrophages (BMMs). RNA-sequencing was performed to evaluate the regulatory mechanisms of MTHFD2 on osteoclastogenesis. Extracellular flux assay, JC-1 staining, and transmission electron microscopy were used to detect mitochondrial function and energy metabolism changes during osteoclast formation. Collagen-induced arthritis (CIA) mice were used to evaluate the therapeutic effect of MTHFD2 knockdown on bone loss. Bone volume and osteoclast counts were quantified by μCT and histomorphometry.ResultsElevated MTHFD2 was observed in RA patients and CIA mice with a positive correlation to bone resorption parameters. During osteoclast formation, MTHFD2 was significantly upregulated in both human CD14 + monocytes and murine BMMs. The application of MTHFD2 inhibitor and MTHFD2 knockdown suppressed osteoclastogenesis, while MTHFD2 overexpression promoted osteoclast differentiation in vitro. RNA-sequencing revealed that MTHFD2 inhibition blocked oxidative phosphorylation (OXPHOS) in osteoclasts, leading to decreased adenosine triphosphate (ATP) production and mitochondrial membrane potential without affecting mitochondrial biogenesis. Mechanistically, inhibition of MTHFD2 downregulated the expression of mitochondrial creatine kinase 1 (CKMT1), which in turn affected phosphocreatine energy shuttle and OXPHOS during osteoclastogenesis. Further, a therapeutic strategy to knock down MTHFD2 in knee joint in vivo ameliorated bone loss in CIA mice.ConclusionsOur findings demonstrate that MTHFD2 is upregulated in RA with relation to joint destruction. MTHFD2 promotes osteoclast differentiation and arthritic bone erosion by enhancing mitochondrial energy metabolism through CKMT1. Thus, targeting MTHFD2 may provide a potential new therapeutic strategy for tackling osteoclastogenesis and bone loss in RA.

Project description:Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by synovitis, bone and cartilage destruction, and increased fracture risk with bone loss. Although disease-modifying antirheumatic drugs have dramatically improved clinical outcomes, these therapies are not universally effective in all patients because of the heterogeneity of RA pathogenesis. Therefore, it is necessary to elucidate the molecular mechanisms underlying RA pathogenesis, including associated bone loss, in order to identify novel therapeutic targets. In this study, we found that Budding uninhibited by benzimidazoles 1 (BUB1) was highly expressed in RA patients' synovium and murine ankle tissue with arthritis. As CD45+CD11b+ myeloid cells are a Bub1 highly expressing population among synovial cells in mice, myeloid cell-specific Bub1 conditional knockout (Bub1ΔLysM) mice were generated. Bub1ΔLysM mice exhibited reduced femoral bone mineral density when compared with control (Ctrl) mice under K/BxN serum-transfer arthritis, with no significant differences in joint inflammation or bone erosion based on a semi-quantitative erosion score and histological analysis. Bone histomorphometry revealed that femoral bone mass of Bub1ΔLysM under arthritis was reduced by increased osteoclastic bone resorption. RNA-seq and subsequent Gene Set Enrichment Analysis demonstrated a significantly enriched nuclear factor-kappa B pathway among upregulated genes in receptor activator of nuclear factor kappa B ligand (RANKL)-stimulated bone marrow-derived macrophages (BMMs) obtained from Bub1ΔLysM mice. Indeed, osteoclastogenesis using BMMs derived from Bub1ΔLysM was enhanced by RANKL and tumor necrosis factor-α or RANKL and IL-1β treatment compared with Ctrl. Finally, osteoclastogenesis was increased by Bub1 inhibitor BAY1816032 treatment in BMMs derived from wildtype mice. These data suggest that Bub1 expressed in macrophages plays a protective role against inflammatory arthritis-associated bone loss through inhibition of inflammation-mediated osteoclastogenesis.

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Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis.

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Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis.

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