Activation of the Peroxisome Proliferator–Activated Receptor γ Coactivator 1β/NFATc1 Pathway in Circulating Osteoclast Precursors Associated With Bone Destruction in Rheumatoid Arthritis

Abstract

Objective Activation of osteoclastogenesis at the bone site in rheumatoid arthritis (RA) is well established. The mechanisms by which circulating osteoclast precursors contribute are still unclear. Peroxisome proliferator–activated receptor γ coactivator 1β (PGC‐1β) is implicated in transcriptional regulation of osteoclastogenesis in mouse models. This study was undertaken to investigate the contribution of PGC‐1β to circulating osteoclast precursors and its link to bone destruction in RA. Methods PGC‐1β expression in RA peripheral blood CD14+ monocytes was increased and showed correlation with joint destruction shown on radiographs. Cells from RA patients or healthy controls were transfected with a lentivirus vector for PGC‐1β gene silencing or overexpression and cultured with macrophage colony‐stimulating factor and RANKL. Bone resorption activity, bone‐degrading enzymes, and signaling molecules were measured in these mature osteoclasts. Results Increased nuclear accumulation of PGC‐1β was observed in RA peripheral blood CD14+ monocytes, and these cells had stronger osteoclastogenesis than in healthy controls. PGC‐1β protein expression was positively correlated with radiographic joint destruction (r = 0.396–0.413; all P < 0.05). PGC‐1β knockdown suppressed (51–82% reduction) the expression of cathepsin K, tartrate‐resistant acid phosphatase (TRAP), and matrix metalloproteinase 9 (MMP‐9), as well as osteoclast differentiation and bone resorption activity. Conversely, PGC‐1β overexpression increased these markers (by 1.5–1.8‐fold) and osteoclastogenesis. VIVIT, an inhibitor of NFATc1 activation, inhibited the effect of overexpressed PGC‐1β by reducing cathepsin K, TRAP, and MMP‐9 expression. Chromatin immunoprecipitation assay and dual‐luciferase reporter gene assay showed PGC‐1β bound to NFATc1 promoter, leading to transcriptional activation. Conclusion Activation of the PGC‐1β/NFATc1 pathway in circulating osteoclast precursors was associated with bone destruction in RA. This may represent a new treatment target.

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases

“…In addition to inhibiting the differentiation of pro-inflammatory macrophages, PGC-1β can also induce osteoclasts differentiation. PGC-1β is induced during the process of osteoclasts differentiation caused by cyclic adenosine monophosphate (cAMP) ( 114 , 118 ). In vitro or in vivo experiments further demonstrated that down-regulation of PGC-1β inhibits mitochondrial biogenesis and osteoclasts differentiation, and osteoclasts function is severely impaired in PGC-1β-deficient mice ( 114 ).…”

Glyburide Regulates UCP1 Expression in Adipocytes Independent of KATP Channel Blockade

“…Results showed that, similar to nitrendipine, both CsA and FK506 treatment effectively blocked the glyburide effect in UCP1 elevation ( Figures 5 C–5F). Moreover, the NFAT inhibitor, VIVIT, which is a cell-permeable peptide inhibitor of nuclear factor of activated T cells (NFAT) that selectively inhibits calcineurin-mediated dephosphorylation of NFAT ( Ma et al., 2019 ), also significantly affected the increase of Ucp1 expression induced by glyburide treatment ( Figure 5 G). Similarly, in white adipocytes, the UCP1 upregulation upon glyburide treatment was also blocked by calcineurin inhibition ( Figure 5 H).…”

Reduced skeletal muscle independently predicts 1-year aggravated joint destruction in patients with rheumatoid arthritis

“…Recently, we reported that increased nuclear accumulation of a metabolic transcription factor peroxisome proliferator-activated receptor γ coactivator 1β (PGC1β) in circulating osteoclast precursors from RA patients promoted osteoclastogenesis and was associated with bone destruction. 35 The study of skeletal-muscle-specific PGC1β transgenic mice showed that sustained over-expression of PGC1β promoted apoptosis and autophagy of myofibers by the regulation of mitochondrial biogenesis, and then caused a progressive decrease in muscle mass. 36 The cross-talk between muscle and bone may also be mediated through endocrine cytokines such as myostatin, irisin, and many others, although the relevance of this communication in RA has not been fully elucidated.…”