Role of NGF‐TrkA signaling in calcification of articular chondrocytes

Nerve growth factor (NGF) is a key regulator of chronic osteoarthritic pain, but the exact targets of NGF action on human articular cartilage is unknown. This study aimed to test the hypothesis that the NGF-tropomyosin receptor kinase A (TrkA) (high-affinity NGF receptor) pathway plays a role in the calcification process of human articular chondrocytes (hACs). A 14-aa small peptide of NGF (Nsp) previously shown to activate NGF signaling in rat PC12 cells was used as an NGF signaling agonist, and recombinant NGF and the pan-Trk inhibitor GNF-5837 were employed as signaling modulating agents. The functional consequences of NGF-TrkA signaling were examined in human healthy articular chondrocytes maintained under conditions supportive of osteogenesis in vitro. The NGF-mimetic bioactivity of Nsp was first confirmed on the basis of maintenance of neurite outgrowth in PC12 cells. Primary human chondrocytes responded to Nsp in vitro. Perturbation of NGF signaling with NGF, Nsp, and GNF-5837 resulted in a strong induction of chondrocyte calcification, and gene expression data suggested that the Indian Hedgehog-parathyroid hormone-related protein signaling axis was involved. These findings suggest functional involvement of NGF signaling in calcification of hACs and the importance of NGF signaling in articular cartilage homeostasis.-Jiang, Y., Tuan, R. S. Role of NGF-TrkA signaling in calcification of articular chondrocytes.