Joint diseases: from connexins to gap junctions

Abstract

Connexons form the basis of hemichannels and gap junctions. They are composed of six tetraspan proteins called connexins. Connexons can function as individual hemichannels, releasing cytosolic factors (such as ATP) into the pericellular environment. Alternatively, two hemichannel connexons from neighbouring cells can come together to form gap junctions, membrane-spanning channels that facilitate cell-cell communication by enabling signalling molecules of approximately 1 kDa to pass from one cell to an adjacent cell. Connexins are expressed in joint tissues including bone, cartilage, skeletal muscle and the synovium. Indicative of their importance as gap junction components, connexins are also known as gap junction proteins, but individual connexin proteins are gaining recognition for their channel-independent roles, which include scaffolding and signalling functions. Considerable evidence indicates that connexons contribute to the function of bone and muscle, but less is known about the function of connexons in other joint tissues. However, the implication that connexins and gap junctional channels might be involved in joint disease, including age-related bone loss, osteoarthritis and rheumatoid arthritis, emphasizes the need for further research into these areas and highlights the therapeutic potential of connexins.

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“…When six units of identical connexins assemble, the resulting connexon is termed homomeric, whereas a connexon formed of different types of connexins is named heteromeric. Following the same rule, gap junctions are homotypic if derived from two identical connexons or heterotypic when two different connexons assemble [73] (Figure 1).…”

“…Connexins are a family of trans-membrane proteins related to several functions, such as, intercellular communication and tissue differentiation. These proteins are best known for being the assembling subunits of connexons, a hexameric structure composed of six units of connexins [72][73][74]. The apposition of connexons in adjacent cells forms intercellular conduits named gap junctions (GJs), which allow the transfer of small molecules, ions and second messengers between cells [75].…”

“…The connexins family comprises 21 genes in the human genome [76], and their genetic expression varies according to the tissue and extracellular conditions. It is noteworthy that several cell types can express more than one type of connexin simultaneously [73,77]. Connexins isoforms possess very similar and conserved structures, consisting of two extracellular loops, four transmembrane domains, one cytoplasmic loop, the C-terminus and the N-terminus [78].…”

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“…Additionally, these channel proteins act as scaffold proteins or signalling hubs via their cytoplasmic domains 4, 21 , regulating different key signalling pathways independently of their channel activity 4, [22][23][24] . Several Cx proteins are expressed in developing and mature skeletal tissues 19,25,26 . However, Cx43 is the major Cx protein expressed in chondrocytes, synovial cells and bone cells 10,12,27-29 and it has been involved in normal development and function of joint tissues 25,[30][31][32] , and in joint disorders including age-related bone loss 33 , rheumatoid arthritis 16,34 and OA progression 10,12,25,27-29 .…”

“…Several Cx proteins are expressed in developing and mature skeletal tissues 19,25,26 . However, Cx43 is the major Cx protein expressed in chondrocytes, synovial cells and bone cells 10,12,27-29 and it has been involved in normal development and function of joint tissues 25,[30][31][32] , and in joint disorders including age-related bone loss 33 , rheumatoid arthritis 16,34 and OA progression 10,12,25,27-29 .…”