Insulin-like growth factor 1 receptor (IGF1R) signaling regulates osterix expression and cartilage matrix mineralization during endochondral ossification
Copyright policy )Insulin-like growth factor 1 receptor (IGF1R) signaling regulates osterix expression and cartilage matrix mineralization during endochondral ossification
Abstract Insulin-like growth factor 1 receptor (IGF1R) signaling is important for bone formation via endochondral ossification. Igf1r deficient mice show proportional dwarfism and alterations in chondrocyte proliferation, hypertrophy and apoptosis within the growth plate. In addition, gene ablation in mouse demonstrated that IGF1R signaling is important for osteoblast mediated bone mineralization. However, the mineralization in the terminal hypertrophic zone of the growth plate is also an essential step in endochondral ossification preceding bone formation. Therefore, we analyzed the influence of IGF1R signaling on this process by using mice with a specific deletion of Igf1r in chondrocytes. Studies in embryonic metatarsal explant cultures showed that mineralization of the terminal hypertrophic zone was strongly reduced when IGF1R signaling was lacking. This decreased mineralization may in part result from the delay in hypertrophic differentiation in the Igf1r deficient metatarsals. However, mineralization was impaired even stronger than hypertrophy, suggesting a mineralization promoting effect of IGF signaling that is independent of hypertrophic differentiation. We found a markedly decreased osterix expression suggesting that osterix is a downstream target of IGF1R in chondrocytes. MMP13 expression was strongly reduced in metatarsals lacking the IGF1R while alkaline phosphatase expression and activity were less affected. We conclude that endogenous IGF1R signaling is important for growth plate matrix remodeling and calcification leading to bone formation and suggest that regulation of osterix expression and its downstream target MMP13 are part of the underlying mechanism.
- University of Cologne Germany
Integrases, Hypertrophy, Alkaline Phosphatase, Bone and Bones, Extracellular Matrix, Receptor, IGF Type 1, Mice, Inbred C57BL, Calcification, Physiologic, Cartilage, Chondrocytes, Organ Culture Techniques, Animals, Newborn, Osteogenesis, Sp7 Transcription Factor, Matrix Metalloproteinase 13, Animals, Collagen Type II, Metatarsal Bones, Signal Transduction, Transcription Factors
Integrases, Hypertrophy, Alkaline Phosphatase, Bone and Bones, Extracellular Matrix, Receptor, IGF Type 1, Mice, Inbred C57BL, Calcification, Physiologic, Cartilage, Chondrocytes, Organ Culture Techniques, Animals, Newborn, Osteogenesis, Sp7 Transcription Factor, Matrix Metalloproteinase 13, Animals, Collagen Type II, Metatarsal Bones, Signal Transduction, Transcription Factors
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