Human Articular Chondrocytes Express Multiple Gap Junction Proteins

Abstract

Osteoarthritis (OA) is the most common joint disease and involves progressive degeneration of articular cartilage. The aim of this study was to investigate if chondrocytes from human articular cartilage express gap junction proteins called connexins (Cxs). We show that human chondrocytes in tissue express Cx43, Cx45, Cx32, and Cx46. We also find that primary chondrocytes from adults retain the capacity to form functional voltage-dependent gap junctions. Immunohistochemistry experiments in cartilage from OA patients revealed significantly elevated levels of Cx43 and Cx45 in the superficial zone and down through the next approximately 1000 μm of tissue. These zones corresponded with regions damaged in OA that also had high levels of proliferative cell nuclear antigen. An increased number of Cxs may help explain the increased proliferation of cells in clusters that finally lead to tissue homeostasis loss. Conversely, high levels of Cxs in OA cartilage reflect the increased number of adjacent cells in clusters that are able to interact directly by gap junctions as compared with hemichannels on single cells in normal cartilage. Our data provide strong evidence that OA patients have a loss of the usual ordered distribution of Cxs in the damaged zones and that the reductions in Cx43 levels are accompanied by the loss of correct Cx localization in the nondamaged areas.

Identification of shoulder osteoarthritis biomarkers: comparison between shoulders with and without osteoarthritis

“…25 More recently, this gap junction protein has been investigated in human knee and femoral head cartilage and found to be significantly elevated in osteoarthritic cartilage versus non-osteoarthritic cartilage ( P < .05 and P < .01, depending on depths of cartilage compared; Kruskal-Wallis test with Dunn’s multiple comparison test). 30 To date, the role of Cx43 in shoulder OA has not been investigated. This study provides strong evidence that Cx43 is significantly increased and has a high predominance in osteoarthritic shoulders compared with non-osteoarthritic shoulders.…”

“…We and others have shown that Cx43 gets up-regulated in cells of the joint during inflammation and OA. 19,25,30,34,49,50 The 19 genes tested in this study were collagen (types I, II, and X), MMP-1, -3, -9, and -13, TIMP-1, -2, and -3, IL-1β, -6, and -17, versican, cyclooxygenase 2 (Cox-2), inducible nitric oxide synthase (iNOS), TNFα, aggrecanase-2 (ADAMTS5), and Cx43 (Table I). Gene expression was normalized to the expression of 18S ribosomal RNA.…”

“…Gap junctions aggregate into large gap junction plaques at the interface of adjacent cells, forming a functional syncytium for the coordinated function of a tissue. 30 Several studies have implicated Cx43 in the etiology of OA. 19,25,49,50 Synovial biopsies from patients with OA were shown to have an increase in Cx43 expression and an increase in the size and number of gap junction plaques.…”

“…19,25 Additionally, the inflammatory cytokine IL-1β has been shown to increase the expression of Cx43 in articular chondrocytes 49,50 and synovial fibroblasts. 34 Recently, a study by Mayan et al 30 investigated cartilage from osteoarthritic knees and femoral heads and found significantly elevated levels of Cx43 compared with non-osteoarthritic cartilage.…”

Cx43- and Smad-Mediated TGF-β/ BMP Signaling Pathway Promotes Cartilage Differentiation of Bone Marrow Mesenchymal Stem Cells and Inhibits Osteoblast Differentiation

“…Cx43 can regulate gene expression and cell cycle progression, and the overexpression of Cx43 has a substantial impact on the structural and functional integrity of human chondrocytes [11]. Transforming growth factor-beta ( TGF-β ), one of the members of the bone morphogenetic protein (BMP) superfamily, is highly expressed in the bone matrix and is closely associated with osteoblast differentiation and bone development [12].…”