Clusterin exerts a cytoprotective and antioxidant effect in human osteoarthritic cartilage

Abstract

Osteoarthritis (OA) is the most common joint disease characterized by destruction of articular cartilage. OA-induced cartilage degeneration causes inflammation, oxidative stress and the hypertrophic shift of quiescent chondrocytes. Clusterin (CLU) is a ubiquitous glycoprotein implicated in many cellular processes and its upregulation has been recently reported in OA cartilage. However, the specific role of CLU in OA cartilage injury has not been investigated yet. We analyzed CLU expression in human articular cartilage in vivo and in cartilage-derived chondrocytes in vitro . CLU knockdown in OA chondrocytes was also performed and its effect on proliferation, hypertrophic phenotype, apoptosis, inflammation and oxidative stress was investigated. CLU expression was upregulated in human OA cartilage and in cultured OA cartilage-derived chondrocytes compared with control group. CLU knockdown reduced cell proliferation and increased hypertrophic phenotype as well as apoptotic death. CLU-silenced OA chondrocytes showed higher MMP13 and COL10A1 as well as greater TNF-α, Nox4 and ROS levels. Our results indicate a possible cytoprotective role of CLU in OA chondrocytes promoting cell survival by its anti-apoptotic, anti-inflammatory and antioxidant properties and counteracting the hypertrophic phenotypic shift. Further studies are needed to deepen the role of CLU in order to identify a new potential therapeutic target for OA.

Transcriptomics‐based analysis of the mechanism by which Wang-Bi capsule alleviates joint destruction in rats with collagen‐induced arthritis

“…The epidermal growth factor receptor (EGFR) system plays important roles in multiple processes, such as the differentiation and proliferation of osteoclasts, osteoblasts and chondrocytes [ 63 ]. Both beta-arrestin-2 (ARRB2) and clusterin (CLU) could inhibit the inflammatory response of chondrocytes, but CLU could also influence the proliferation and differentiation of chondrocytes [ 64 , 65 ]. In this study, we found that the expression of Cxcl13, Chad, Arrb2, Fgf9, Egfr and Clu was obviously suppressed in rats with CIA, but WB treatment increased it to a certain degree.…”

Exploring the translational potential of clusterin as a biomarker of early osteoarthritis

“…The levels of COMP, a cartilage degradation marker, in the explant secretome were increased two-fold under IL-1β and TNF-α stimulation versus the control. In contrast to the above results, human OA articular chondrocytes cultured in vitro were reported to express higher CLU mRNA and protein levels (detected in total cell lysates) compared to untreated controls [ 12 ] We propose that lower sCLU secretion by OA cartilage could be caused by an interruption at the transcriptional level, or by CLU being retained intracellularly during stress, rather than by degradation of extracellular sCLU.…”

“…Inflammation in OA is different from rheumatoid arthritis (RA), psoriatic arthritis (PsA), and other autoimmune joint diseases – it is defined as low-grade inflammation but chronic and persistent [ 9 , 10 ]. All of these changes occurring over time lead to joint destruction, pain, and functional disability [ 11 , 12 ]. The mechanisms and pathways involved in the pathogenesis and progression of OA are not fully understood but senescence [ 13 ], abnormal mechanical load [ 14 ], metabolic dysfunction [ 15 , 16 ], and low-grade inflammation [ 10 , 17 ] are all thought to be important contributing factors.…”

Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

“…The results showed significantly increased expression of CLU in LF samples; however, there was no marked difference in CLU levels in blood samples from the LFH group and non-LFH group. CLU upregulation has been reported in local tissue, such as OA-induced cartilage degeneration 38 , osteoporotic disease 39 , tears of dry eye 19 and brain tissues of AD patients. The results suggested specifically high expression of CLU in LF tissues prone to fibrosis.…”