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We previously showed that type X collagen, a marker of late stage chondrocyte hypertrophy (associated with endochondral ossification), is constitutively expressed by mesenchymal stem cells (MSCs) from osteoarthritis patients and this may be related to Naproxen (Npx), a nonsteroidal anti-inflammatory drug used for therapy. Hedgehog (HH) signaling plays an important role during the development of bone. We tested the hypothesis that Npx affected osteogenic differentiation of human MSCs through the expression of Indian hedgehog ( IHH ), Patched-1 ( PTC1 ) and GLI family members  GLI1 ,  GLI2, GLI3 in vitro .    Methods  MSCs were cultured in osteogenic differentiation medium without (control) or with 0.5 μM Npx. The expression of collagen type X, alpha 1 ( COL10A1 ), alkaline phosphatase ( ALP ), osteopontin ( OPN ), osteocalcin ( OC ), collagen type I, alpha 1 ( COL1A1 ) was analyzed with real-time reverse transcription (RT) PCR, and the ALP activity was measured. The osteogenesis of MSCs was monitored by mineral staining and quantification with alizarin red S. To examine whether Npx affects osteogenic differentiation through HH signaling, the effect of Npx on the expression of  IHH ,  GLI1 ,  GLI2 ,  GLI3  and  PTC1  was analyzed with real-time RT PCR. The effect of cyclopamine (Cpn), a HH signaling inhibitor, on the expression of  COL10A1 ,  ALP ,  OC  and  COL1A1  was also determined.    Results  When MSCs were cultured in osteogenic differentiation medium, Npx supplementation led to a significant decrease in  ALP  gene expression as well as its activity, and had a tendency to decrease mineral deposition. It also decreased the expression of  COL1A1  significantly. In contrast, the gene expression of  COL10A1  and  OPN  were upregulated significantly by Npx. No significant effect was found on  OC  expression. The expression of  IHH ,  PTC1 ,  GLI1,  and  GLI2  was increased by Npx, while no significant difference was observed on  GLI3  expression. Cpn reversed the effect of Npx on the expression of  COL10A1 ,  ALP ,  OPN  and  COL1A1 .    Conclusions  These results indicate that Npx can affect gene expression during osteogenic differentiation of MSCs, and downregulate mineral deposition in the extracellular matrix through IHH signaling. Therefore, Npx could affect MSC-mediated repair of subchondral bone in OA patients.

Naproxen affects osteogenesis of human mesenchymal stem cells via regulation of Indian hedgehog signaling molecules