Researchers show that the protein CCN4 positively regulates the generation of cartilage matrix, which are depleted in osteoarthritis.
Osteoarthritis is the most common musculoskeleton disease. It is caused by the loss of articular cartilage and subchondral tissue, which causes pain, stiffness and a loss of mobility in joints. Adult cartilage does not readily regenerate, and the disease is often treated by implantation of patient-derived ‘chondrocyte cells’ – the cells that make up cartilage. As a result, the mechanisms behind the differentiation of stem cells into chondrocytes have attracted a great deal of interest. Researchers at Okayama University Graduate School of Medicine and colleagues now report, “For the first time, we showed that CCN4 exerts a positive effect on [transforming growth factor beta 3] TGF-?3-induced chondrogenesis by modulating TGF-?3 binding to the surface of [human bone marrow stromal cells ] hBMSCs and enhancing its downstream signalling.”
The CCN family includes 6 proteins some of which have known links to the generation of bone and cartilage but so far the role of CCN4 in chondrogenesis has been unclear. In the current study, Yuya Yoshioka, Mitsuaki Ono and colleagues at Okayama University Graduate School of Medicine, Japan, and the National Institutes of Health in Maryland, US, investigated hBMSCs that either over- or under-expressed the CCN4. By analysing micromass cultures of the hBMSCs, they found that cells overexpressing CCN4, led to enhanced TGF-?3-induced processes that produce cartilage. Where CCN4 was knocked out these processes were inhibited.
The effect of CCN4 on the chondrogenic differentiation of hBMSCs in vitro. Twenty eight days after chondrogenic induction, histological analysis of hBMSC micromass cultures was performed for detection of glycosaminoglycans with safranin O staining, or type II collagen alpha 1 by immunohistochemistry. Micromass cultures with adCCN4-transduced (CCN4 overexpressed, left) shows intense immunostaining for collagen type II. In contrast chondrocyte-like cells were nearly absent, and ACAN and COL2A1 transcript levels were also significantly down-regulated in siCCN4-transduced (CCN4 knock down, right) hBMSCs micromasses
Image Credit: Okayama University