Down‐regulation of cathepsin K in synovium leads to progression of osteoarthritis in rabbits

Abstract

Objective. The hypothesis of this study was that synovial factors playing a pivotal role in the pathogenesis of osteoarthritis (OA) and thus gene expression in the synovium would be altered at the initial stage of OA. The aims of this study were to identify the candidate genes in synovium related to OA initiation, to evaluate cartilage degeneration after knockdown of the gene using small interfering RNA (siRNA) gene silencing in the knee joints at the initial stage of OA, and to determine the potential role of the knocked-down gene in OA initiation.Methods. Genes overexpressed in synovium at the initial stage of disease in a rabbit model of anterior cruciate ligament transection (ACLT)-induced OA were identified using the suppression subtractive hybridization technique and differential screening. Candidate gene expression in the synovium of the knees of rabbits with OA was manipulated with electroporation-assisted siRNA transduction 4 times before and after operation. Four weeks after surgery, histologic analysis was performed.Results. Cathepsin K gene and protein expression was significantly up-regulated in synovium at the initial stage of OA in rabbits. Down-regulation of cathepsin K in synovium at the initial stage of OA significantly accelerated cartilage degeneration.Conclusion. These results indicate that cathepsin K plays a protective role in cartilage degeneration at the initial stage of OA. We believe that the current results obtained from models of the early phase of OA will provide useful information for developing a novel strategy to prevent disease progression.

Carrageenan-induced transient inflammation in a rabbit knee model: molecular changes consistent with an early osteoarthritis phenotype

“…The mRNA levels for cathepsin K showed significant upregulation in the first week, reached peak levels at 2 weeks and then returned to near-normal levels by 4 weeks. Interestingly, following ACL transection in a rabbit model of OA development, cathepsin K gene expression levels were shown to be significantly increased by 7 days after surgery [45]. Thus, the expression of cathepsin K followed patterns similar to those observed for MMPs and the pro-inflammatory cytokines.…”

“…Some studies suggest that downregulation of this protease may lead to a delay in the OA development, as it suppresses both inflammation and osteoclastic bone resorption [46]. However, studies using small interfering RNAs have demonstrated that in the initial development of OA, suppression of cathepsin K leads to increased expression of MMP-13 which in turn leads to cartilage degeneration, which is the hallmark of OA progression [45].…”

Electroporation of Craniofacial Mesenchyme

“…The majority of these studies were gene therapy studies, such as siRNA or protein delivery into chondrogenic cell lines, or, animal models of arthritis [11][12][13] . In other systems, such as chicken or mouse, electroporation of facial mesenchyme has been challenging (personal communications, Dept of Craniofacial Development, KCL).…”

siRNA therapy for cancer and non-lethal diseases such as arthritis and osteoporosis

“…Cathepsin K gene and protein expression is upregulated in the synovium in a rabbit model of anterior cruciate ligament transection-induced OA. Downregulation of cathepsin K by an electroporation-assisted siRNA transduction in the synovium leads to OA progression in rabbits, indicating that cathepsin K is involved in cartilage degeneration [61]. So far, siRNA therapy of OA (e.g., ad-siRNA (NF-kB p65) or electrotransfer of siRNA against cathepsin K) is in various preclinical development stages [60,61] and no clinical trials have been reported.…”