Gap junctions in skeletal development and function

University of Maryland, Baltimore, Baltimore, Maryland, United States
Biochimica et Biophysica Acta (Impact Factor: 4.66). 01/2006; 1719(1-2):69-81. DOI: 10.1016/j.bbamem.2005.10.012
Source: PubMed


Gap junctions play a critical role in the coordinated function and activity of nearly all of the skeletal cells. This is not surprising, given the elaborate orchestration of skeletal patterning, bone modeling and subsequent remodeling, as well as the mechanical stresses, strains and adaptive responses that the skeleton must accommodate. Much remains to be learned regarding the role of gap junctions and hemichannels in these processes. A common theme is that without connexins none of the cells of bone function properly. Thus, connexins play an important role in skeletal form and function.

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Available from: Roberto Civitelli, Jan 15, 2014
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    • "The expression of Cx45, Cx46 and, more recently, Cx37 has also been demonstrated in bone cells (Kruger et al., 2000; Stains and Civitelli, 2005; Paic et al., 2009; Chaible et al., 2011; Pacheco-Costa et al., 2014). In particular, Cx37 is required for osteoclast differentiation and mice lacking Cx37 exhibit high bone mass due to defective bone resorption (Pacheco-Costa et al., 2014). "
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    ABSTRACT: Cell function and survival are controlled by intracellular signals, and modulated by surrounding cells and the extracellular environment. Connexin channels participate in these processes by mediating cell-to-cell communication. In bone cells, gap junction channels were detected in the early 1970s, and are present among bone resorbing osteoclasts, bone forming osteoblasts, and osteocytes - mature osteoblasts embedded in the mineralized matrix. These channels are composed mainly by Cx43, although the expression of other connexins (45, 46, and 37) has also been reported. It is now believed that undocked Cx43 hemichannels (connexons) formed in unopposed cell membranes facing the extracellular environment participate in the interaction of bone cells with the extracellular environment, and in their communication with neighboring cells. Thus, we and others demonstrated the presence of active hemichannels in osteoblastic and osteocytic cells. These hemichannels open in response to pharmacological and mechanical stimulation. In particular, preservation of the viability of osteoblasts and osteocytes by the anti-osteoporotic drugs bisphosphonates depends on Cx43 expression in vitro and in vivo, and is mediated by undocked hemichannels. Cx43 hemichannels are also required for the release of prostaglandins and ATP by osteocytes, and for cell survival induced by mechanical stimulation in vitro. Moreover, they are required for the anti-apoptotic effect of parathyroid hormone in osteoblastic cells. This review summarizes the current knowledge on the presence and function of undocked connexons, and the role of hemichannel regulation for the maintenance of bone cell viability and, potentially, bone health.
    Full-text · Article · Apr 2014 · Frontiers in Physiology
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    • "Gap junctions are composed of two hemichannels (connexons) each of which is formed by six protein subunits, called connexins. The connexons of adjacent cells can form an intercellular channel which allows propagation of ions, such as calcium ions, metabolites and second messengers of up to 1.2 kDa between the cells [12]. The functional role of hemichannels and of gap junctional communication of osteoblast and osteocytes has been studied intensively [13], and recently it has been shown that amorphous calcium phosphate alters cx43-mediated gap junctional communication and cell function of dental pulp cells by increasing local calium concentrations [15]. "
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    ABSTRACT: In order to investigate the effects of different degrees of bioactivity of xerogels on connexin 43 (cx43) signaling of osteoclasts a cell culture approach was developed. Cells isolated from peripheral blood mononuclear cells were cultured in combination with the xerogels and were harvested for further investigations on day 1, day 5, and day 10. By means of quantitative PCR increased cx43 mRNA levels and coincident decreasing mRNA levels of the calcium sensing receptor, TRAP, and Cathepsin K were detected with increasing bioactivity of the xerogel samples. Additionally, osteoclasts cultured on tissue culture plates were used to perform principle investigations on cell differentiation by means of transmission electron microscopy, life cell imaging, and immunofluorescence, and the results demonstrated that cx43-signaling could be attributed to migration and fusion of osteoclast precursors. Therefore, the positive correlation of cx43 expression with high xerogel bioactivity was caused by proceeding differentiation of the osteoclasts. Finally, the presently observed pattern of cx43 signaling refers to strong effects regarding bioactivity on cx43-associated cell differentiation of osteoclasts influenced by extracellular calcium ions.
    Full-text · Article · Nov 2013 · Biomaterials
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    • "At least three connexins, CX43, CX45 and CX46 are expressed in bone cells with CX43 being the most abundant. There is solid evidence for an important role of CX43 in skeletal development and the function and survival of osteoblasts and osteocytes [23,24,25,26]. Data from in vitro studies supported a role for CX43 and gap junctional intracellular communication during osteoblastic cell differentiation and coordinated cell responsiveness [27,28]. "
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    ABSTRACT: Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. CMD can be inherited in an autosomal dominant (AD) trait or occur after de novo mutations in the pyrophosphate transporter ANKH. Although the autosomal recessive (AR) form of CMD had been mapped to 6q21-22 the mutation has been elusive. In this study, we performed whole-exome sequencing for one subject with AR CMD and identified a novel missense mutation (c.716G>A, p.Arg239Gln) in the C-terminus of the gap junction protein alpha-1 (GJA1) coding for connexin 43 (Cx43). We confirmed this mutation in 6 individuals from 3 additional families. The homozygous mutation cosegregated only with affected family members. Connexin 43 is a major component of gap junctions in osteoblasts, osteocytes, osteoclasts and chondrocytes. Gap junctions are responsible for the diffusion of low molecular weight molecules between cells. Mutations in Cx43 cause several dominant and recessive disorders involving developmental abnormalities of bone such as dominant and recessive oculodentodigital dysplasia (ODDD; MIM #164200, 257850) and isolated syndactyly type III (MIM #186100), the characteristic digital anomaly in ODDD. However, characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with the recessive Arg239Gln Cx43 mutation. Bone remodeling mechanisms disrupted by this novel Cx43 mutation remain to be elucidated.
    Full-text · Article · Aug 2013 · PLoS ONE
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