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The melanocortin system in articular chondrocytes: Melanocortin receptors, pro‐opiomelanocortin, precursor proteases, and a regulatory effect of α‐melanocyte–stimulating hormone on proinflammatory cytokines and extracellular matrix components
Ist Teil von
Arthritis and rheumatism, 2009-10, Vol.60 (10), p.3017-3027
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2009
Link zum Volltext
Quelle
Access via Wiley Online Library
Beschreibungen/Notizen
Objective
The pro‐opiomelanocortin (POMC)–derived neuropeptide α‐melanocyte–stimulating hormone (α‐MSH) mediates its effects via melanocortin (MC) receptors. This study was carried out to investigate the expression patterns of the MC system and the effects of α‐MSH in human articular chondrocytes.
Methods
Articular chondrocytes established from human osteoarthritic joint cartilage were analyzed by reverse transcription–polymerase chain reaction (RT‐PCR) and Western blotting for the expression of MC receptors, POMC, and prohormone convertases (PCs). MC‐1 receptor (MC‐1R) expression in articular cartilage was further studied by immunohistochemistry. Ca2+ and cAMP assays were used to monitor α‐MSH signaling, while studies of α‐MSH function were performed in cultures with chondrocyte micromass pellets stimulated with α‐MSH. Expression of cytokines and extracellular matrix (ECM) components was determined by real‐time RT‐PCR, Western immunoblotting, and enzyme‐linked immunosorbent assays.
Results
MC‐1R expression was detected in articular chondrocytes in vitro and in articular cartilage in situ. In addition, expression of transcripts for MC‐2R, MC‐5R, POMC, and PCs was detected in articular chondrocytes. Stimulation with α‐MSH increased the levels of intracellular cAMP, but not Ca2+, in chondrocytes. Both messenger RNA and protein expression of various proinflammatory cytokines, collagens, matrix metalloproteinases (MMPs), and SOX9 was modulated by α‐MSH.
Conclusion
Human articular chondrocytes are target cells for α‐MSH. The effects of α‐MSH on expression of cytokines and MMPs suggest that this neuropeptide plays a role in inflammatory and degenerative processes in cartilage. It is conceivable that inflammatory reactions can be mitigated by the induction of endogenous MCs or administration of α‐MSH to the affected joints. The induction pattern of regulatory and structural ECM components such as collagens as well as SOX9 and anabolic and catabolic cytokines points to a function of α‐MSH as a trophic factor in skeletal development during endochondral ossification rather than as a factor in homeostasis of permanent cartilage.