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Induction of nerve growth factor expression and release by mechanical and inflammatory stimuli in chondrocytes: possible involvement in osteoarthritis pain.

Abstract : INTRODUCTION: Nerve growth factor (NGF) level is increased in osteoarthritis (OA) joint and is involved in pain associated with OA. Stimuli responsible for NGF stimulation in chondrocytes are unknown. We investigated whether mechanical stress and pro-inflammatory cytokines may influence NGF synthesis by chondrocytes. METHODS: Primary cultures of human OA chondrocytes, newborn mouse articular chondrocytes or cartilage explants were stimulated by increasing amounts of IL-1beta, prostaglandin E2 (PGE2), visfatin / nicotinamide phosphoribosyltransferase (NAMPT) or by cyclic mechanical compression (0.5 Hz, 1 MPa). Before stimulation, chondrocytes were pretreated with indomethacin, Apo866, a specific inhibitor of NAMPT enzymatic activity, or transfected by siRNA targeting visfatin/NAMPT. mRNA NGF levels were assessed by real-time quantitative PCR and NGF released into media was determined by ELISA. RESULTS: Unstimulated human and mouse articular chondrocytes expressed low levels of NGF (19.2 +/- 8.7 pg/mL, 13.5 +/- 1.0 pg/mL and 4.4 +/- 0.8 pg/mL/mg tissue for human and mouse articular chondrocytes and costal explants, respectively). Mechanical stress induced NGF release in conditioned media. When stimulated by IL-1beta or visfatin/NAMPT, a pro-inflammatory adipokine produced by chondocytes in response to IL-1beta, a dose-dependent increase in NGF mRNA expression and NGF release in both human and mouse chondrocyte conditioned media was observed. Visfatin/NAMPT is also an intracellular enzyme acting as the rate-limiting enzyme of the generation of NAD. The expression of NGF induced by visfatin/NAMPT was inhibited by Apo866, whereas IL-1beta-mediated NGF expression was not modified by siRNA targeting visfatin/NAMPT. Interestingly, PGE2, which is produced by chondrocytes in response to IL-1beta and visfatin/NAMPT, did not stimulate NGF production. Consistently, indomethacin, a cyclooxygenase inhibitor, did not counteract IL-1beta-induced NGF production. CONCLUSIONS: These results show that mechanical stress, IL-1beta and extracellular visfatin/NAMPT, all stimulated the expression and release of NGF by chondrocytes and thus suggest that the overexpression of visfatin/NAMPT and IL-1beta in OA joint and the increased mechanical loading of cartilage may mediate OA pain via the stimulation of NGF expression and release by chondrocytes.
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Emilie Pecchi, Sabrina Priam, Marjolaine Gosset, Audrey Pigenet, Laure Sudre, et al.. Induction of nerve growth factor expression and release by mechanical and inflammatory stimuli in chondrocytes: possible involvement in osteoarthritis pain.. Arthritis Research and Therapy, BioMed Central, 2014, 16 (1), pp.R16. ⟨10.1186/ar4443⟩. ⟨inserm-00956364⟩

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