Osteopontin Promotes Oncostatin M Production in Human Osteoblasts: Implication of Rheumatoid Arthritis Therapy

Abstract

Accumulating evidence indicates that subchondral bone might play an essential role in rheumatoid arthritis (RA). Osteopontin (OPN) induces the production of an important proinflammatory cytokine involved in the pathogenesis of RA. This study evaluated the activation of oncostatin M (OSM) by OPN in human primary osteoblasts to understand RA pathogenesis and characterized the intracellular signaling pathways involved in this activation. Quantitative PCR, ELISA, and Western blot results indicated that stimulation of human primary osteoblasts with OPN induces OSM expression through αvβ3 integrin/c-Src/platelet-derived growth factor receptor transactivation/MEK/ERK. Treatment of osteoblasts with OPN also increased c-Jun phosphorylation, AP-1 luciferase activity, and c-Jun binding to the AP-1 element on the OSM promoter, as demonstrated using chromatin immunoprecipitation assay. Moreover, inhibition of OPN expression using lentiviral-OPN short hairpin RNA resulted in the amelioration of articular swelling, cartilage erosion, and OSM expression in the ankle joint of mice with collagen-induced arthritis as shown using microcomputed tomography and immunohistochemistry staining. Our results imply that OSM expression in osteoblasts increases in response to OPN-induced inflammation in vitro. Finally, lentiviral-OPN short hairpin RNA ameliorates the inflammatory response and bone destruction in mice with collagen-induced arthritis. Therefore, OPN may be a potential therapeutic target for RA.

Osteopontin Promotes Bone Destruction in Periapical Periodontitis by Activating the NF-κB Pathway

“…It contains seven exons and six introns, and is encoded on chromosome 4. In the bone, OPN is secreted by osteoblasts, osteoclasts, and bone cells, and plays a very important role in bone resorption [21][22][23][24][25]. In healthy bones, OPN is located at sites of new bone formation.…”

“…When the bone is absorbed, OPN is released from the bone matrix and adheres to osteoblasts. Therefore, OPN is generally considered to promote bone mineralization [24][25][26]34]. However, Huang reported that OPN inhibited the proliferation and differentiation of osteoblasts in vitro, and that the overexpression of OPN inhibited mineral deposition in bone tissue [21].…”

CCN1 Promotes VEGF Production in Osteoblasts and Induces Endothelial Progenitor Cell Angiogenesis by Inhibiting miR-126 Expression in Rheumatoid Arthritis

“…(32) In the current study, mCT imaging and IHC staining of the ankle joints showed articular cartilage erosion in mice with CM was also applied to 5-day-old fertilized chick embryos for 3 days. CAMs were then examined by microscopy and photographed.…”

“…The CIA mouse model protocol followed that as detailed in previously published work. (31,32) First, 0.1 mL of an emulsion containing 100 mg of bovine type II collagen (CII) dissolved at a concentration of 2 mg/mL in 0.1 M acetic acid and complete Freund's adjuvant was injected intradermally into the base of the tail. Second, 2 weeks after the primary immunization, a booster injection of 100 mg CII dissolved and emulsified 1:1 with incomplete Freund's adjuvant was administered into the hind paw.…”

“…(32) We therefore examined VEGF production in osteoblasts after CCN1 treatment. Treatment of osteoblasts (MG-63 and hFOB cells) increased VEGF mRNA expression and protein secretion in a concentration-dependent manner ( Fig.…”