Protective effects of Nebivolol against interleukin-1β (IL-1β)-induced type II collagen destruction mediated by matrix metalloproteinase-13 (MMP-13)

Abstract

The pathological progression of osteoarthritis (OA) involves degradation of articular cartilage matrix. Type II collagen is the main component of cartilage matrix, which is degraded by pro-inflammatory cytokines such as IL-1β mediated by MMP-13. Nebivolol, a licensed drug used for the treatment of hypertension in clinics, displays its anti-inflammatory capacity in various conditions. However, whether Nebivolol has a protective effect on cartilage matrix degradation has not been reported before. In this study, we investigated the effects of Nebivolol on regulating the expression of MMP-13 and degradation of type II collagen. Our results indicate that Nebivolol alleviated the increase in gene expression, protein expression, and activity of MMP-13 induced by IL-1β. Importantly, IL-1β strikingly reduced the levels of type II collagen in cell culture supernatants, which was reversed by treatment with Nebivolol in a dose-dependent manner. Mechanistically, Nebivolol was found to alleviate the increased levels of phosphorylated IκBα and reduced levels of total IκBα induced by IL-1β, which subsequently mitigated p65 nuclear translocation and the transcriptional activity of NF-κB. Furthermore, our results indicated that IL-1β treatment resulted in a significant increase in expression of the transcriptional factor interferon regulatory factor-1 (IRF-1) at both the mRNA and protein levels, which was significantly ameliorated by treatment with Nebivolol. The combination of these findings suggests that Nebivolol can potentially be applied in human OA treatment.

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

“…Dysfunction of sympathetic neurotransmission is an early pathologic event in RA and in rodent models of RA (2,17,18,23,(87)(88)(89)(90)(91)(92). Consistent with these reports, the densities of sympathetic nerves in the synovium are similar in control and AA rats shortly after disease onset, but dramatically reduced at acute and chronic disease.…”

“…The b 2 -AR-mediated actions of SH1293 on multiple targets in bone (i.e., osteoblast, osteoclasts, adipocytes, fibroblasts, inflammatory infiltrates) may have direct and indirect actions with opposing actions on bone metabolism occurring across disease progression. Consistent with indirect b 2 -AR actions on skeletal tissues, Li et al (89) found protective effects of the b-blocker, nebivolol against IL-1b-induced type II collagen destruction mediated by matrix metalloproteinase-13, whereas direct effects of b 2 -ARs on fibroblasts are anti-fibrotic.…”

Protective Effects of Garlic-Derived S-Allylmercaptocysteine on IL-1β-Stimulated Chondrocytes by Regulation of MMPs/TIMP-1 Ratio and Type II Collagen Expression via Suppression of NF-κB Pathway

“…Type II collagen is the main component of cartilage matrix, which degraded in OA pathological progression [ 28 ]. In this study, we investigated the effects of SAMC on regulating the degradation of type II collagen.…”

MicroRNA-128-3p suppresses interleukin-1β-stimulated cartilage degradation and chondrocyte apoptosis via targeting zinc finger E-box binding homeobox 1 in osteoarthritis

“…The protein bands were visualized using the ECL system (Bio-Rad). For MMP-13 in cell culture supernatants, cultured media were collected from the supernatant by centrifugation, followed by concentrated with trichloroacetic acid (TCA) and acetone as described previously [ 18 ].…”