Elevated Expression of CCN3 in Articular Cartilage Induces Osteoarthritis in Hip Joints Irrespective of Age and Weight Bearing

• Published in: International journal of molecular sciences Vol. 23; no. 23; p. 15311
• Main Authors: Hirose, Kazuki, Kuwahara, Miho, Nakata, Eiji, Tetsunaga, Tomonori, Yamada, Kazuki, Saiga, Kenta, Takigawa, Masaharu, Ozaki, Toshifumi, Kubota, Satoshi, Hattori, Takako
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.12.2022; MDPI
• Subjects: ADAMTA4/5; Age; Age differences; Aggrecan; Aggrecans - metabolism; Animals; Arthritis; Biomedical materials; Cartilage; Cartilage (articular); Cartilage diseases; Cartilage, Articular - metabolism; Cell cycle; cellular communication network factor 3 (CCN3); Chondrocytes; Chondrocytes - metabolism; Collagenase 3; Femur; Gene expression; Hip joint; Hip Joint - metabolism; hip osteoarthritis; Humans; Humerus; IL-1β; Interleukin 6; Joint replacement surgery; Joints (anatomy); Knee; Mechanical loading; Mice; Osteoarthritis; Osteoarthritis - metabolism; p16; Phenotypes; Roughening; Senescence; senescence-associated secretory phenotype (SASP); Staining; Total hip arthroplasty; Weight-Bearing; X ray analysis; TNFα; cellular communication network factor 3 (CCN3); p16; hip osteoarthritis; ADAMTA4/5; cartilage; weight-bearing; aging; IL-6; Mankin score; non-weight-bearing; senescence-associated secretory phenotype (SASP)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232315311

Osteoarthritis (OA) occurs not only in the knee but also in peripheral joints throughout the whole body. Previously, we have shown that the expression of cellular communication network factor 3 (CCN3), a matricellular protein, increases with age in knee articular cartilage, and the misexpression of CCN3 in cartilage induces senescence-associated secretory phenotype (SASP) factors, indicating that CCN3 promotes cartilage senescence. Here, we investigated the correlation between CCN3 expression and OA degenerative changes, principally in human femoral head cartilage. Human femoral heads obtained from patients who received total hip arthroplasty were categorized into OA and femoral neck fracture (normal) groups without significant age differences. Gene expression analysis of RNA obtained from femoral head cartilage revealed that and expression in the non-weight-bearing part was significantly higher in the OA group than in the normal group, whereas the weight-bearing OA parts and normal cartilage showed no significant differences in the expression of these genes. The expression of , however, was significantly higher in weight-bearing OA parts compared with normal weight-bearing parts, and was also higher in weight-bearing parts compared with non-weight-bearing parts in the OA group. In contrast, OA primary chondrocytes from weight-bearing parts showed higher expression of , , , and than chondrocytes from the corresponding normal group, and higher and in the non-weight-bearing part compared with the corresponding normal group. expression was significantly lower in the non-weight-bearing group in OA primary chondrocytes than in the corresponding normal chondrocytes. The expression level of did not show significant differences between the weight-bearing part and non-weight-bearing part in both OA and normal primary chondrocytes. Immunohistochemical analysis showed accumulated CCN3 and aggrecan neoepitope staining in both the weight-bearing part and non-weight-bearing part in the OA group compared with the normal group. The CCN3 expression level in cartilage had a positive correlation with the Mankin score. X-ray analysis of cartilage-specific CCN3 overexpression mice (Tg) revealed deformation of the femoral and humeral head in the early stage, and immunohistochemical analysis showed accumulated aggrecan neoepitope staining as well as CCN3 staining and the roughening of the joint surface in Tg femoral and humeral heads. Primary chondrocytes from the Tg femoral head showed enhanced expression of , , , , and , and decreased expression of and . These findings indicate a correlation between OA degenerative changes and the expression of CCN3, irrespective of age and mechanical loading. Furthermore, the Mankin score indicates that the expression level of Ccn3 correlates with the progression of OA.