The Role of THBS-3 in the Regulation of Cartilage Angiogenesis and Fibrosis Via the TGF-β/Smad2/3 Pathway in Osteoarthritis

Objective Angiogenesis plays a crucial role in osteoarthritis (OA) by promoting inflammatory cell invasion, supporting neo-innervation and joint tissue fibrosis, and contributing to structural damage and pain. Thrombospondin-3 (THBS-3) is highly expressed in OA cartilage. However, the mechanisms responsible for upregulation of THBS-3 in OA are unclear. Design OA chondrocytes and a collagen-induced osteoarthritis (CIOA) mouse model were used as in vitro and in vivo models, respectively. THBS-3 was used to treat chondrocytes in vitro and in vivo . To explore the mechanism of THBS-3 in chondrocytes treatment, we pretreated chondrocytes with a THBS-3 inhibitor and assessed cartilage metabolic function and then analyzed related indicators of vascularization and chondrofibrosis. Results Proteomics revealed higher THBS-3 expression in the cartilage of CIOA mice than in that of normal mice. Compared with those from healthy individuals, chondrocytes from OA patients presented significantly increased protein expression of THBS-3. In both in vivo and in vitro experiments, THBS-3 promoted matrix metalloproteinase-13 and disintegrin and metalloprotease with thrombospondin-5, suppressed aggrecan, and promoted the vascularization and chondrofibrosis in dysfunctional chondrocytes from osteoarthritic chondrocytes. THBS-3 activated the transforming growth factor-beta (TGF-β) signaling pathway. The pretreatment of OA chondrocytes with a TGF-β inhibitor before THBS-3 exposure reversed these changes. Conclusion THBS-3 promotes the angiogenesis and fibrosis of chondrocytes by activating the TGF-β/Smad2/3 signaling pathway.