TrkC protects against osteoarthritis progression by maintaining articular cartilage homeostasis.

Abstract

Osteoarthritis (OA) is a degenerative disease with a series of metabolic changes accompanied by chondrocyte apoptosis. Chondrocytes express multiple receptors for neurotrophin, however, the role of neurotrophin receptor in chondrocyte metabolism remains unelucidated. Here, we first clarify the role of neurotrophin 3 (NT3) and its receptor tropomyosin receptor kinase C (TrkC) of chondrocytes in OA pathogenesis, using inducible TrkC-deficient mice (TrkC^fl/fl; Col2a1-CreER^T2 mice). Our findings show that TrkC levels are decreased in the chondrocytes and cartilage of patients with OA and OA-model mice. Chondrocyte-specific TrkC deficiency aggravates cartilage destruction during OA development. However, intra-articular TrkC-overexpressing adeno-associated virus (AAV) injection delays experimental OA progression. TrkC deficiency leads to decreased anabolic and increased catabolic activities in chondrocytes and stimulates chondrocyte apoptosis, thereby accelerating OA progression. Whereas TrkC overexpression rescues the imbalance between extracellular matrix synthesis and degradation and chondrocyte apoptosis through PI3K/Akt signaling. NT3, a multifunctional protein with high affinity for TrkC, effectively protects against cartilage degeneration in OA models in vitro and in vivo and relieves pain sensitivity in mice with OA. Our results indicate that TrkC is crucial for maintaining cartilage homeostasis and OA progression. Targeting TrkC with NT3 could be a novel strategy for OA treatment.