Abstract
Objectives: Rheumatoid arthritis (RA) is characterized by defective bone repair and excessive destruction and ankylosing spondylitis (AS) by increased ectopic bone formation with syndesmophytes. Since TNF-α and IL-17A are involved in both diseases, this study investigated their effects on the osteogenic differentiation of isolated human bone marrow-derived mesenchymal stem cells (hMSCs).Methods: Differentiation of hMSCs into osteoblasts was induced in the presence or absence of IL-17A and/or TNF-α. Matrix mineralization (MM) was evaluated by alizarin red staining and alkaline phosphatase (ALP) activity. mRNA expression was measured by qRT-PCR for bone morphogenetic protein (BMP)-2 and Runx2, genes associated with osteogenesis, DKK-1, a negative regulator of osteogenesis, Schnurri-3 and receptor activator of nuclear factor kappa B ligand (RANKL), associated with the cross talk with osteoclasts, and TNF-α receptor type I and TNF-α receptor type II (TNFRII).Results: TNF-α alone increased both MM and ALP activity. IL-17A alone increased ALP but not MM. Their combination was more potent. TNF-α alone increased BMP2 mRNA expression at 6 and 12 h. These levels decreased in combination with IL-17A at 6 h only. DKK-1 mRNA expression was inhibited by TNF-α and IL-17A either alone or combined. Supporting an imbalance toward osteoblastogenesis, RANKL expression was inhibited by TNF-α and IL-17A. However, TNF-α but not IL-17 alone decreased Runx2 mRNA expression at 6 h. In parallel, TNF-α but not IL-17 alone increased Schnurri-3 expression with a synergistic effect with their combination. This may be related to an increase of TNFRII overexpression.Conclusion: IL-17 increased the effects of TNF-α on bone matrix formation by hMSCs. However, IL-17 decreased the TNF-α-induced BMP2 inhibition. Synergistic interactions between TNF-α and IL-17 were seen for RANKL inhibition and Schnurri-3 induction. Such increase of Schnurri-3 may in turn activate osteoclasts leading to bone destruction as in RA. Conversely, in the absence of osteoclasts, this could promote ectopic bone formation as in AS.
Highlights
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that contributes to the pathogenesis of several inflammatory diseases [1, 2]
Since TNF-α and IL-17A are involved in both diseases, this study investigated their effects on the osteogenic differentiation of isolated human bone marrow-derived mesenchymal stem cells
Matrix mineralization (MM) was evaluated by alizarin red staining and alkaline phosphatase (ALP) activity. mRNA expression was measured by qRT-PCR for bone morphogenetic protein (BMP)-2 and runt-related transcription factor-2 (Runx2), genes associated with osteogenesis, Dickkopf 1 (DKK-1), a negative regulator of osteogenesis, Schnurri-3 and receptor activator of nuclear factor kappa B ligand (RANKL), associated with the cross talk with osteoclasts, and TNF-α receptor type I and TNF-α receptor type II (TNFRII)
Summary
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that contributes to the pathogenesis of several inflammatory diseases [1, 2]. In rheumatoid arthritis (RA), there is excessive bone destruction and defective bone repair leading to massive joint damage, while in ankylosing spondylitis (AS) there is excessive but ectopic ossification leading to syndesmophytes combined with systemic bone loss [1, 3,4,5]. Increased levels of IL-17 in both diseases have suggested its contribution to these bone defects [4]. We have previously found that addition of inhibitors of Abbreviations: AS, ankylosing spondylitis; BMP2, bone morphogenetic protein 2; DKK-1, dickkopf 1; MSC, mesenchymal stem cell; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor kappa B ligand; Runx, runt-related transcription factor-2; Shn, Schnurri-3. IL-17A and TNF-α alone or even better in combination, decreases bone destruction in an ex vivo model of RA [12]
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