Abstract
Interleukin 17 (IL-17) stimulates the osteogenic differentiation of progenitor cells in vitro through a synergy with bone morphogenetic protein (BMP)-2. This study investigates whether the diverse responses mediated by IL-17 in vivo also lead to enhanced BMP-2-induced bone formation. Since IL-17 is known to induce osteoclastogenesis, we studied the interactions between IL-17 and BMP-2 in ceramic scaffolds either or not carrying a coating with the bisphosphonate zoledronic acid (ZOL). Histological evaluation revealed that IL-17 alone did not induce any osteoclasts at day 10. On the other hand, BMP-2 clearly stimulated early tissue ingrowth and osteoclastogenesis. Both of these processes were blocked in presence of ZOL. IL-17 signaling restored early vascularized connective tissue formation and osteoclastogenesis induced by BMP-2 in ZOL-coated scaffolds. After 12 weeks, the bone volume induced by co-delivery of BMP-2 and IL-17 was doubled as compared to that induced by BMP-2 alone. We conclude that IL-17 has osteo-stimulatory effects through a synergy with bone-inductive BMP-2. Although local and single application of IL-17 does not mediate osteoclast formation, it could promote other processes involved in bone formation such as connective tissue ingrowth. The use of IL-17 may contribute to the development of improved bone graft substitutes.
Highlights
There is a need for bone substitutes that can decrease the reliance on autologous bone grafts for repair of bone defects[1]
The zoledronic acid (ZOL) was strongly bound to the biphasic calcium phosphate (BCP), which corresponds with its high affinity for hydroxyapatite[40]
BCP scaffolds with a suboptimal amount of bone morphogenetic protein (BMP)-2, either or not combined with interleukin 17 (IL-17), were investigated in subcutaneous pockets in rabbits
Summary
There is a need for bone substitutes that can decrease the reliance on autologous bone grafts for repair of bone defects[1]. This study investigates a potential role of the pro-inflammatory cytokine interleukin 17 (IL-17) as a modulator of BMP-2-induced new bone formation. This study showed attenuated calvarial defect healing when IL-17 was added to ceramic bone grafts[19] This suggests that IL-17 exerts a negative effect on the osteogenic response, its influence on bone regeneration could be heavily dependent on the context of IL-17 signaling. It has been shown that MSCs recruited from either bone marrow, circulation, or local vascularized tissue will home to bone scaffolds following ectopic implantation[27,28] This methodology allows for better study of osteoinductive pathways compared to bone defect models, where native bone-inductive growth factors and cells support healing partially through an osteoconductive mechanism[26]. To assess the role of osteoclasts in IL-17-mediated responses, scaffolds were used that were either or not coated with ZOL
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