Novel role of CCN3 that maintains the differentiated phenotype of articular cartilage

Abstract

Knowledge of the microenvironment of articular cartilage in health and disease is the key to accomplishing fundamental disease-modifying treatments for osteoarthritis. The proteins comprising the CCN Family are matricellular proteins with a remarkable relevance within the context of cartilage metabolism. CCN2 displays a great capability for regenerating articular cartilage, and CCN3 has been shown to activate the expression of genes related to articular chondrocytes and to repress genes related to endochondral ossification in epiphyseal chondrocytes. Moreover, mice lacking CCN3 protein have been shown to display ostearthritic changes in their knee articular cartilage. In this study, we employed a monoiodoacetic acid (MIA)-induced osteoarthritic model to investigate whether osteoarthritic changes in the cartilage are reciprocally accompanied by CCN3 down-regulation and an inducible overexpression system to evaluate the effects of CCN3 on articular chondrocytes in vitro. Finally, we also investigated the effects of exogenous CCN3 in vivo during the early stages of MIA-induced osteoarthritis. We discovered that CCN3 is expressed by articular chondrocytes in normal rat knees, whereas it is rapidly down-regulated in osteoarthritic knees. In vitro, we also discovered that CCN3 increases the proteoglycan accumulation, the gene expression of type II collagen, tenascin-C and lubricin, as well as the protein production of tenascin-C and lubricin in articular chondrocytes. In vivo, it was discovered that exogenous CCN3 increased tidemark integrity and produced an increased production of lubricin protein. The potential utility of CCN3 as a future therapeutic agent and possible strategies to improve its therapeutic functions are also discussed.

A friend in knee: CCN3 may inhibit osteoarthritis progression

“…Furthermore, assessing the role of CCN3 in other models of OA would provide additional evidence supporting the role of CCN3 in OA progression. Nonetheless, this study by Janune et al ( 2016 ) is consistent with the notion that CCN3 or CCN3-derived peptides could be used in the future as a potential therapy for OA.…”

“…Gaining a better understanding of these processes is crucial in developing a viable therapy for OA. A recent report in Journal of Bone Mineral Metabolism by Janune et al (J Bone Miner Metab 35:582–597, 2016 ) suggests a novel role for CCN3 in maintaining the differentiated phenotype of articular cartilage. This report suggests that CCN3, a member of the CCN family of matricellular proteins, is important for proteoglycan accumulation, as well as expression of type II collagen, tenascin C, and lubricin in vitro.…”

“…Given the importance of CCN3 in the microenvironment of articular cartilage, Janune et al ( 2016 ) sought to uncover more about the potential role of CCN3 in the progression of OA. The authors aimed to investigate the reciprocal regulation of CCN3 during osteoarthritic changes in a monoiodoacetic acid (MIA)-induced model of OA, as well as evaluate the in vitro effects of CCN3 overexpression on articular chondrocytes.…”

Metabolic regulation of the CCN family genes by glycolysis in chondrocytes

“…It may be assumed that the observed CCN3 induction is a protective response against energy or nutrition shortage. Interestingly, application of MIA to articular cartilage in vivo results in immediate expenditure of CCN3 in articular cartilage and production of CCN3 in clustering chondrocytes, suggesting its role in cartilage protection (Janune et al 2017). CCN3 is shown to maintain the differentiated phenotype of articular chondrocytes, repressing their proliferation to save energy consumption (Janune et al 2011).…”

Regenerating CNS myelin: Emerging roles of regulatory T cells and CCN proteins

“…CCN3 is essential for maintaining HSC long term repopulating activity and bone marrow engraftment (Gupta et al, 2007). Finally, CCN3 is also known to participate in chondrogenesis (Heath et al, 2008;Hoshijima et al, 2012;Janune et al, 2017Janune et al, , 2011Kawaki et al, 2008;Lafont et al, 2005;Roddy and Boulter, 2015), osteogenesis (Heath et al, 2008;Matsushita et al, 2013;Minamizato et al, 2007;Ouellet and Siegel, 2012;Rydziel et al, 2007) and dentin regeneration .…”