Age-related changes in gap junctional intercellular communication in osteoblastic cells

Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California-Davis, Davis, California.
Journal of Orthopaedic Research (Impact Factor: 2.99). 12/2012; 30(12):1979-84. DOI: 10.1002/jor.22172
Source: PubMed


Aging demonstrates deleterious effects upon the skeleton which can predispose an individual to osteoporosis and related fractures. Despite the well-documented evidence that aging decreases bone formation, there remains little understanding whereby cellular aging alters skeletal homeostasis. We, and others, have previously demonstrated that gap junctions-membrane-spanning channels that allow direct cell-to-cell conductance of small signaling molecules-are critically involved in osteoblast differentiation and skeletal homeostasis. We examined whether the capacity of rat osteoblastic cells to form gap junctions and respond to known modulators of gap junction intercellular communication (GJIC) was dependent on the age of the animal from which they were isolated. We observed no effect of age upon osteoblastic Cx43 mRNA, protein or GJIC. We also examined age-related changes in PTH-stimulated GJIC. PTH demonstrated age-dependent effects upon GJIC: Osteoblastic cells from young rats increased GJIC in response to PTH, whereas there was no change in GJIC in response to PTH in osteoblastic cells from mature or old rats. PTH-stimulated GJIC occurred independently of changes in Cx43 mRNA or protein expression. Cholera toxin significantly increased GJIC in osteoblastic cells from young rats compared to those from mature and old rats. These data demonstrate an age-related impairment in the capacity of osteoblastic cells to generate functional gap junctions in response to PTH, and suggest that an age-related defect in G protein-coupled adenylate cyclase activity at least partially contributes to decreased PTH-stimulated GJIC. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1979-1984, 2012.

Download full-text


Available from: Damian C Genetos, Oct 01, 2015
1 Follower
21 Reads
  • Source
    • "There have not been many studies looking at the effects of aging on the junctions present within the testis though there have been a number done on other tissues. For example, in both spinal ganglia (Procacci, 2008) and osteoblasts [23] there is a decrease in the ability to form gap junctions with age. In addition to the decrease we saw in proteins involved in adherens junctions, a range of small GTPases that are involved in junction assembly, e.g. in the recruitment of cadherins to the adherens junctions found between Sertoli and germ cells, were similarly decreased in aged spermatocytes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: With increasing age comes many changes in the testis, including germ cell loss. Cell junctions in the testis tether both seminiferous epithelial and germ cells together and assist in the formation of the blood-testis barrier (BTB), which limits transport of biomolecules, ions and electrolytes from the basal to the adluminal compartment and protects post-meiotic germ cells. We hypothesize that as male rats age the proteins involved in forming the junctions decrease and that this alters the ability of the BTB to protect the germ cells. Pachytene spermatocytes were isolated from Brown Norway rat testes at 4 (young) and 18 (aged) months of age using STA-PUT velocity sedimentation technique. RNA was extracted and gene expression was assessed using Affymetrix rat 230 2.0 whole rat genome microarrays. Microarray data were confirmed by q-RT-PCR and protein expression by Western blotting. Of the genes that were significantly decreased by at least 1.5 fold, 70 were involved in cell adhesion; of these, at least 20 are known to be specifically involved in junction dynamics within the seminiferous epithelium. The mRNA and protein levels of Jam2, Ocln, cdh2 (N-cadherin), ctnna (α-catenin), and cldn11 (involved in adherens junctions), among others, were decreased by approximately 50% in aged spermatocytes. In addition, the GTPases Rac1 and cdc42, involved in the recruitment of cadherins to the adherens junctions, were similarly decreased. It is therefore not surprising that with lower expression of these proteins that the BTB becomes diminished with age. We saw, using a FITC tracer, a gradual collapse of the BTB between 18 and 24 months. This provides the opportunity for harmful substances and immune cells to cross the BTB and cause the disruption of spermatogenesis that is observed with increasing age.
    PLoS ONE 12/2013; 8(12):e84354. DOI:10.1371/journal.pone.0084354 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gap junctions (GJ) and hemichannels (HC) formed from the protein subunits called connexins are transmembrane conduits for the exchange of small molecules and ions. Connexins and another group of HC-forming proteins, pannexins comprise the two families of transmembrane proteins ubiquitously distributed in vertebrates. Most cell types express more than one connexin or pannexin. While connexin expression and channel activity may vary as a function of physiological and pathological states of the cell and tissue, only a few studies suggest the involvement of pannexin HC in acquired pathological conditions. Importantly, genetic mutations in connexin appear to interfere with GJ and HC function which results in several diseases. Thus connexins could serve as potential drug target for therapeutic intervention. Growing evidence suggests that diseases resulting from HC dysfunction might open a new direction for development of specific HC reagents. This review provides a comprehensive overview of the current studies of GJ and HC formed by connexins and pannexins in various tissue and organ systems including heart, central nervous system, kidney, mammary glands, ovary, testis, lens, retina, inner ear, bone, cartilage, lung and liver. In addition, present knowledge of the role of GJ and HC in cell cycle progression, carcinogenesis and stem cell development is also discussed.
    Archives of Biochemistry and Biophysics 03/2012; 524(1):2-15. DOI:10.1016/ · 3.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Connexin43 (Cx43) is the most abundant gap junction protein expressed in bone cells and plays a central role in cell-to-cell communication in the skeleton. Findings of the last decade uncovered functions of Cx43 hemichannels expressed on unopposed plasma cell membranes as mediators of the communication between bone cells and their extracellular milieu. Additionally, through its cytoplastmic C-terminus domain, Cx43 serves as a scaffolding protein that associates with structural and signaling molecules leading to regulation of intracellular signaling, independent of channel activity. This perspective discusses the evidence demonstrating that via these diverse mechanisms Cx43 is a key component of the intracellular machinery responsible for signal transduction in bone in response to pharmacologic, hormonal and mechanical stimuli. This advance in the knowledge of the role of connexins increases our understanding of the pathophysiological mechanisms that regulate bone cell function and provides new opportunities to treat bone diseases.
    Bone 10/2012; 52(1):157-166. DOI:10.1016/j.bone.2012.09.030 · 3.97 Impact Factor
Show more