Abstract
BackgroundWe have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA). The exact mechanism of AD in promoting joint destruction remains unclear. Osteopontin (OPN) is required for osteoclast recruitment. We hypothesized that AD exacerbates bone erosion by inducing OPN expression in synovial tissue. This study aimed to evaluate a novel role for AD in RA.MethodsThe serum levels of AD and OPN were determined in 38 patients with RA, 40 patients with osteoarthritis (OA), and 20 healthy controls using enzyme-linked immunosorbent assay (ELISA). AD and OPN production were measured by double immunofluorescence in RA and OA synovial tissue. Quantitative real-time PCR and immunofluorescence were used to evaluate the mRNA and protein expression levels of OPN in RA synovial fibroblasts (RASFs) and OA synovial fibroblasts after pre-incubation with AD, respectively. Migration of the RAW264.7 osteoclast precursor cell line was assessed using the Transwell migration assay and co-culture system. Bone destruction and osteoclastogenesis were assessed by immunohistochemical staining, microcomputed tomography and tartrate-resistant acid phosphatase (TRAP) staining in AD-treated collagen-induced arthritis (CIA) mice with or without OPN silencing. The expression levels of OPN and integrin αvβ3 in the ankle joint tissues of the mice were examined by double immunofluorescence.ResultsOur results indicated that the AD and OPN expression levels increased noticeably and were associated with each other in the RA serum. The AD distribution was coincident with that of OPN in the RA synovial tissue. AD stimulation of RASFs increased OPN production in a dose-dependent manner. AD-treated RASFs promoted RAW264.7 cell migration, and the effect was blocked with a specific antibody against OPN. Silencing of OPN using lentiviral-OPN short hairpin RNA reduced the number of TRAP-positive osteoclasts and the extent of bone erosion in the AD-treated CIA mice. When bound to integrin αvβ3, OPN functions as a mediator of AD and osteoclasts.ConclusionsOur study provides new evidence of AD involvement in bone erosion. AD induces the expression of OPN, which recruits osteoclasts and initiates bone erosion. These data highlight AD as a novel target for RA treatment.
Highlights
We have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA)
AD is correlated with OPN in serum and synovial tissue of patients with RA To examine the effects of AD and OPN during the development of RA, we first assessed the relationship between AD and OPN expression in patients with RA
Our results show that integrin αvβ3 is detected coincidently with OPN, which further confirms that the effect of ADinduced OPN on osteoclast precursor migration and progression of bone erosion is mediated through integrin αvβ3
Summary
We have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA). We hypothesized that AD exacerbates bone erosion by inducing OPN expression in synovial tissue. Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by chronic synovial inflammation, joint destruction, progressive disability, systemic complications and socioeconomic costs [1, 2]. The precise aetiology of RA remains elusive, substantial evidence has suggested that T cells, B cells and the complex interaction of multiple proinflammatory cytokines play critical roles in the pathophysiology of RA [3, 4]. Adipose tissue is a ubiquitous tissue, and accumulative evidence shows that the dominant cell type in adipose tissue, the adipocyte, can synthesize and release pro-inflammatory molecules, complement factors, signalling molecules, growth factors and adhesion molecules, contributing to a wide spectrum of diseases that include cardiovascular and metabolic complications and inflammation-related and immune-related disorders [5, 6]
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