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- Title
IL-6-accelerated calcification by induction of ROR2 in human adipose tissue-derived mesenchymal stem cells is STAT3 dependent.
- Authors
Fukuyo, Shunsuke; Yamaoka, Kunihiro; Sonomoto, Koshiro; Oshita, Koichi; Okada, Yosuke; Saito, Kazuyoshi; Yoshida, Yasuhiro; Kanazawa, Tamotsu; Minami, Yasuhiro; Tanaka, Yoshiya
- Abstract
Objective. The mechanisms of ectopic calcification in inflammatory diseases are poorly understood. We investigated the effects of inflammatory cytokines on the mechanisms of calcification in human adipose tissue-derived mesenchymal stem cells (hADSCs).Methods. The effects of inflammatory cytokines were evaluated using hADSCs cultured in osteoblast induction medium. mRNA expression was measured by real-time PCR and protein levels were measured by western blotting. Cell mineralization was evaluated by Alizarin Red S staining.Results. In hADSCs, administration of IL-6/soluble IL-6 receptor (sIL-6R), TNF or IL-1β accelerated calcification through enhanced expression of an osteoblast differentiation marker, runt-related transcription factor 2 (RUNX2). IL-6/sIL-6R had the greatest effect. The transcription of mRNA for receptor tyrosine kinase-like orphan receptor 2 (ROR2), involved in the non-canonical wingless-type (WNT) MMTV integration site pathway, was increased, while β-catenin expression, an essential factor in the canonical WNT signalling pathway for osteoblast differentiation, did not change. Suppression of signal transducer and activator of transcription 3 (STAT3), but not STAT1, by small interfering RNA (siRNA) exerted a strong inhibitory effect on RUNX2 and ROR2 expression, and inhibited accelerated calcification.Conclusion. IL-6/sIL-6R stimulation accelerated the ROR2/WNT5A pathway in hADSCs in a STAT3-dependent manner, resulting in augmented calcification. These results suggest that the mechanisms of ectopic calcification accelerated by IL-6 in hADSCs may be involved in chronic inflammatory tissues and that IL-6 inhibitors may be beneficial in the treatment of ectopic calcification in inflammatory diseases.
- Subjects
JAPAN; STEM cells; ACADEMIC medical centers; ADIPOSE tissues; ANALYSIS of variance; CELL culture; CYTOKINES; IMMUNOHISTOCHEMISTRY; INFLAMMATION; INTERLEUKINS; POLYMERASE chain reaction; RESEARCH funding; STATISTICS; T-test (Statistics); WESTERN immunoblotting; DATA analysis; OXIDATIVE stress; CALCINOSIS; IN vitro studies; PHYSIOLOGY
- Publication
Rheumatology, 2014, Vol 53, Issue 7, p1282
- ISSN
1462-0324
- Publication type
Article
- DOI
10.1093/rheumatology/ket496