Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis

Abstract

Objectives: To study the expression of cysteine proteinases, particularly cathepsin K, and their extracellular inhibitor cystatin C in articular cartilage of transgenic Del1 mice which harbour a short deletion mutation in a type II collagen transgene and are predisposed to early onset osteoarthritis. Methods: Northern analysis was used to measure mRNA levels of cathepsins B, H, K, L, and S, and cystatin C in total RNA extracted from knee joints of Del1 mice, using their non-transgenic litter mates as controls. Immunohistochemistry and morphometry was used to study the distribution of cathepsin K and cystatin C in the knee joints. Results: Up regulation of cathepsin K mRNA expression was seen in the knee joints of transgenic Del1 mice at the onset of cartilage degeneration. Cathepsin K was found near sites of matrix destruction in articular chondrocytes, particularly in clusters of proliferating cells, and in calcified cartilaginous matrix. In intact articular cartilage of control animals, cathepsin K was only seen in a small number of chondrocytes. Upon aging, control animals also developed osteoarthritis, which was accompanied by increased cathepsin K expression. Cystatin C was mostly localised in and around chondrocytes located in calcified cartilage, with no obvious association with the onset of cartilage degeneration. Conclusion: The temporospatial distribution of cathepsin K in osteoarthritic cartilage suggests a role for this enzyme in the pathogenesis of osteoarthritis. Because cathepsin K can digest cartilage matrix components it may contribute to the development of osteoarthritic lesions. These data may provide new clues for the development of treatments aimed at preventing cartilage degeneration.

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

“…Cathepsin K has been considered to be a key enzyme involved in the degradation of articular cartilage, at least in the advanced and/or end stages of OA. Up-regulation of cathepsin K was observed not only in articular cartilage but also in the synovial tissue of mice and humans with advanced OA (26,32,33). Inhibition of cathepsin K could potently suppress autoimmune inflammation of the joints as well as osteoclastic bone resorption in autoimmune arthritis (34).…”

Trichostatin A inhibits expression of cathepsins in experimental osteoarthritis

“…Among them, cathepsin K received main attention as it is capable to cleave type I and II collagens as well as aggrecan [5,6]. Elevated gene expression of cathepsin K has been noted in articular cartilage in transgenic mouse for OA, supporting the correlation between cathepsin K and OA [7]. The role of cathepsins B, L and S in degradation of ECM also have been well documented [8][9][10].…”

“…The role of cathepsins B, L and S in degradation of ECM also have been well documented [8][9][10]. In light of the importance of cysteine proteases in cartilage destruction, studies focused on the expression of cysteine proteases and over-expression of cathepsins were noted in arthritis [7,11]. Up-regulation of cathepsins in arthritic cartilage always accompanied with the down-regulation of cystatin C, which is an endogenous inhibitor of cysteine proteinase [12].…”

Identification of Genes Regulated by IL-1β Using Integrative microRNA and mRNA Genomic Analysis in Human Articular Chondrocytes

“…By using integrative approach using simultaneous miRNA-mRNA profil- Member of the trypsin family of serine proteases; regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins; increased in the knee and TM joints of mouse OA models in early stages of the disease (53); HtrA1-generated aggrecan fragments containing the VQTV (356) neoepitope were significantly more abundant in osteoarthritic cartilage compared with cartilage from healthy joints (54) Binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance; mutation leads to achondroplasia; induces premature senescence in chondrocytes, manifested as growth arrest, alteration of cellular shape, and loss of the extracellular matrix (55) Expressed in bone marrow and cord blood mononuclear cells; regulates chondrogenesis as a novel autocrine factor, but not hypertrophic maturation of chondrocytes during cartilage development (56) Encodes a DNA-binding transcription factor which may regulate morphogenesis, and differentiation; the encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development; persistent expression in chondrogenic cells results in overall chondrodysplasia with delayed cartilage hypertrophy, mineralization, and ossification in mouse embryo (57) An antioxidant enzyme that disproportionate reactive oxygen species; increased by IL-1 and IL-6 dose and time-dependently in bovine chondrocytes (58) A catalytic subunit of the protein kinase complex important for cell cycle G1 phase progression; overexpression leads to resistance to FGF-induced p107 dephosphorylation and growth arrest (59) A major glycoprotein of the vascular endothelium,and a component of the transforming growth factor (TGF) beta receptor complex; mutations in this gene cause hereditary hemorrhagic telangiectasia; expressed on human chondrocytes at levels comparable with endothelial cells and forms higher order complexes with the type I and II TGFβ receptors (60) A member of the Bar subclass of homeobox transcription factors which play a role in developing teeth and craniofacial mesenchyme of neural crest origin; expressed in the developing joint and articular cartilage and has an inhibitory effect on chondrogenic initiation (61) A lysosomal cysteine proteinase involved in bone remodeling and resorption; induced in phenotypically altered chondrocytes in human OA and animal OA model (62,63); chemical inhibitor results in mild to moderate beneficial effects on gross and histopathological parameters of OA and reduction of biomarkers of collagen type I and II degradation in the canine partial medial meniscectomy model of OA (64) ing and bioinformatic analysis, we further attempted to explore the miRNA target with more precision. Total RNA was isolated from IL-1β treated monolayer chondrocytes obtained from donors different from those that were used in miRNA microarray.…”