Connexins in the skeleton

Abstract

Shaping of the skeleton (modeling) and its maintenance throughout life (remodeling) require coordinated activity among bone forming (osteoblasts) and resorbing cells (osteoclasts) and osteocytes (bone embedded cells). The gap junction protein connexin43 (Cx43) has emerged as a key modulator of skeletal growth and homeostasis. The skeletal developmental abnormalities present in oculodentodigital and craniometaphyseal dysplasias, both linked to Cx43 gene (GJA1) mutations, demonstrate that the skeleton is a major site of Cx43 action. Via direct action on osteolineage cells, including altering production of pro-osteoclastogenic factors, Cx43 contributes to peak bone mass acquisition, cortical modeling of long bones, and maintenance of bone quality. Cx43 also contributes in diverse ways to bone responsiveness to hormonal and mechanical signals. Skeletal biology research has revealed the complexity of Cx43 function; in addition to forming gap junctions and "hemichannels", Cx43 provides a scaffold for signaling molecules. Hence, Cx43 actively participates in generation and modulation of cellular signals driving skeletal development and homeostasis. Pharmacological interference with Cx43 may in the future help remedy deterioration of bone quality occurring with aging, disuse and hormonal imbalances.

Keywords: Bone; Cx37; Cx43; Gap junction; Signal transduction.

Fig. 1

Structure and components of gap junctions. Gap junctions are composed of 6 connexin subunits. (Left) Connexins have 4 transmembrane domains (TM1–4), two extracellular loops (EL1–2), a cytoplasmic loop (CL) and cytoplasmic N (NT) and C-termini (CT). Protein complexes known to associate with the Cx43 CT are shown in blue. (Middle) Six connexin monomers assemble to form a connexon, which when inserted at the plasma membrane is called a “hemichannel”, which allows diffusion of small molecules between the cytoplasm and the extracellular space. (Right) When two connexons on the plasma membrane of adjacent cells dock, a continuous channel is formed between the two cells, permitting direct cell-to-cell communication.

Fig. 2

An elaborate network of gap junction coupled cells allows communication among bone embedded osteocytes, surface osteoblast and osteoprogenitors.

Fig. 3

Cx43 in cultured MC3T3 osteoblastic cells. Immunofluorescence labeling of Cx43 (green), the actin cytoskeleton (red), and the nuclei (blue). Scale bar = 20 µm.

Fig. 4

Cx43 in cortical bone. Immunofluorescence of Cx43 (red) with DAPI stained nuclei (blue). The boxed area enlarged on the right shows extensive Cx43 signal in surface cells and throughout the osteocytic network. Scale bar = 20 µm.