The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes

Abstract

Chondrocytes in cartilage and bone cells population express connexin43 (Cx43) and gap junction intercellular communication (GJIC) is essential to synchronize cells for coordinated electrical, mechanical, metabolic and chemical communication in both tissues. Reduced Cx43 connectivity decreases chondrocyte differentiation and defective Cx43 causes skeletal defects. The carboxy terminal domain (CTD) of Cx43 is located in the cytoplasmic side and is key for protein functions. Here we demonstrated that chondrocytes from the CTD-deficient mice, K258stop/Cx43KO and K258stop/K258stop, have reduced GJIC, increased rates of proliferation and reduced expression of collagen type II and proteoglycans. We observed that CTD-truncated mice were significantly smaller in size. Together these results demonstrated that the deletion of the CTD negatively impacts cartilage structure and normal chondrocyte phenotype. These findings suggest that the proteolytic cleavage of the CTD under pathological conditions, such as under the activation of metalloproteinases during tissue injury or inflammation, may account for the deleterious effects of Cx43 in cartilage and bone disorders such as osteoarthritis.

Multifaceted Roles of Connexin 43 in Stem Cell Niches

“…More recently, the Cx43 CT has been shown to bind to multiple signaling proteins needed for optimal osteoblast function, namely PKCδ, ERK, and β catenin [ 50 ••]. As a result, the K258stop/Cx43KO mice have several defects in osteoblast proliferation, differentiation, and collagen deposition [ 51 •]. This clearly emphasizes the importance of the Cx43 CT, possibly as a docking hub for multiple proteins needed for different signaling cascades regulating cell function, and this may be relevant to Cx43 regulation of stem and progenitor cells.…”

Cysteine residues in the cytoplasmic carboxy terminus of connexins dictate gap junction plaque stability

“…This is the first report showing that stability of the gap junction nexus can be altered through mutation without removing binding domains from the Cx43 CT and will allow testing for tissue level effects of nexus stability in vivo with particular attention to tissues in which connexin subdomains have functional significance such as neuro-gliovascular system, cardiovascular system, bone and cartilage development, tumor growth/metastasis, and skin-wound healing. The CT of Cx43 or Cx32 has been shown to be important in these tissues (Gellhaus et al , 2004; Gago-Fuentes et al , 2016; Hammond et al , 2016; Katoch et al , 2015). The cysteine residues of the CT of Cx43 (and some residues on either side of the cysteines) are conserved among rat and human sequences.…”

Dendritic Cell Migration Toward CCL21 Gradient Requires Functional Cx43

“…We also observed ex-vivo Ag-dependent T-cell activation by BMDCs from our two genetically modified Cx43 mouse models. Both mouse strains, whereby Cx43 +/− mice are known to express half of the amount of Cx43 and Cx43 K258/− mice to express Cx43 channels that lack post-translational regulation, have revealed phenotypic alterations in cartilage structure (Gago-Fuentes et al, 2016 ) and inflammation (Sarieddine et al, 2009 ; Kozoriz et al, 2010 ; Morel et al, 2016 ). Thus, genetic manipulations of Cx43 do not confirm observations made in DCs treated with connexin blockers and indicate that Cx43 expression is not prerequisite for their Ag presenting cell function (Glass et al, 2015 ).…”