Syndecan-2 Regulates Integrin-β1 to Influence the Abnormal Subchondral Bone in Early-stage Knee Osteoarthritis

Background: In osteoarthritis (OA), syndecan-2 (SDC-2) was found to be mainly present in blood vessels. This study was designed to investigate the expression of SDC-2 in subchondral bone during the early stage of knee OA and a possible mechanism underlying its role in early-stage OA.

Methods: A rat knee OA model was established by performing the destabilization of the medial meniscus (DMM) surgery. In the early OA model at 2 weeks, 4 weeks, and 6 weeks time points, the platelet-derived growth factor-BB (PDGF-BB), platelet-derived growth factor receptor β (PDGFR-β), SDC-2, and integrin-β1 in the subchondral bone were observed using immunofluorescence. In vitro experiments, different concentrations of TR-14035 (0, 2.5, 5 µM) were used to treat the interleukin (IL)-1β-induced osteoclasts to analyze the changes of SDC-2 and p-Akt (Ser473)/Akt, and then cultured with endothelial progenitor cells (EPCs) to analyze the changes of PDGF-BB/PDGFR-β and p-NF-κB p65 (Ser536)/NF-κB p65 in EPCs. Moreover, exogenous SDC-2 was used to analyze its effects on integrin-β1 in IL-1β-induced osteoclasts and articular chondrocytes. Additionally, inhibition of integrin-β1 in early-stage OA rats was used to observe the changes of cartilage degeneration using Safranin O and Collagen Ⅱ staining.

Results: The expressions of PDGF-BB, PDGFR-β, SDC-2, and integrin-β1 in the subchondral bone of OA rats were significantly increased over time compared with the sham rats (P < 0.05). In the IL-1β-induced osteoclasts, TR-14035 treatment significantly reduced the IL-1β-induced increase in SDC-2, Integrin β1, and p-Akt(Ser473)/Akt in a dose-dependent manner (P < 0.05). The PDGF-BB/PDGFR-β and p-NF-κB p65 (ser536)/NF-κB p65 pathways in EPCs were significantly enhanced after coculturing with IL-1β-induced osteoclasts, but inhibition of Integrin β1 in IL-1β-induced osteoclasts attenuated the above effects (P < 0.05). Moreover, inhibition of Integrin β1 improved the cartilage degradation in IL-1β-induced articular chondrocytes and early-stage OA rats, but exogenous SDC-2 attenuated these effects.

Conclusion: This study showed SDC-2 regulated integrin-β1 in the IL-1β-induced osteoclasts to affect the endothelial PDGF-BB/PDGFR-β signaling. Inhibition of Integrin β1 improved the cartilage degradation in IL-1β-induced articular chondrocytes and early-stage OA rats. This study suggested SDC-2/integrin-β1 played a critical role in subchondral bone during the early-stage OA.

Endothelial progenitor cells; Integrin-β1; Osteoarthritis; Osteoclasts; Subchondral bone; Syndecan-2.