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

ObjectiveAngiogenesis 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.DesignOA chondrocytes and a collagen-induced osteoarthritis (CIOA) mouse model were used as <i>in vitro</i> and <i>in vivo</i> models, respectively. THBS-3 was used to treat chondrocytes <i>in vitro</i> and <i>in vivo</i>. 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.ResultsProteomics 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 <i>in vivo</i> and <i>in vitro</i> 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.ConclusionTHBS-3 promotes the angiogenesis and fibrosis of chondrocytes by activating the TGF-β/Smad2/3 signaling pathway.