Regulation of Osteoblast Differentiation and Function by Connexin 43

Summary

Principal Investigator: Joseph P Stains
Abstract: DESCRIPTION (provided by applicant): Diseases of low bone mass, like age-dependent osteoporosis, have a profound impact on society. Current therapies for the restoration or maintenance of bone mass are limited and focus primarily on the attenuation of osteoclast activity. The gap junction protein connexin 43, which permits the direct cell-to-cell communication of signals between osteoblasts and osteocytes, has been shown to play an important role in osteoblast/osteocyte function and the acquisition of peak bone mass. Despite the clear importance of connexin 43 in skeletal function, key molecular details of how connexin 43 regulates bone mass acquisition, osteoblast differentiation and osteoblast/osteocyte function are unknown. Rational therapies to impact skeletal diseases, like osteoporosis, cannot be designed without understanding the underlying molecular mechanisms affecting bone mass acquisition. Indeed, any intervention intended to impact the entire bone forming unit to reverse or slow down skeletal diseases will require an understanding of the intricate methods of intercellular exchange of information, such as those afforded by connexin 43, among osteoblasts and osteocytes for optimal efficacy. In this grant application, we hypothesize that connexin 43 regulates osteogenic differentiation and function, and ultimately bone quality, by regulating the recruitment and activation of signal transduction cascades that converge upon the master regulators of osteoblastogenesis, Runx2 and Osterix. This grant has two specific aims to address this hypothesis. (Specific Aim 1) To determine the contribution of Cx43 and Cx43-dependent signaling to osteogenic differentiation at the level of Runx2 and/or Osterix;(Specific Aim 2) To determine the requirements for both signal complex recruitment to connexin 43 and second messenger permeability by connexin 43 for downstream modulation of osteogenic differentiation and signaling. We will use cell and molecular biology, as well as in vivo genetic models to resolve key knowledge gaps, regarding how connexin 43 regulates bone. By defining these mechanisms, we will gain critical understanding of how connexin 43 ultimately affects osteoblast function and bone mass acquisition. Indeed our long-term goal is to apply the knowledge gleaned from these studies to modulate connexin 43 expression or connexin 43-dependent signaling cascades, either physiologically or pharmacologically, to increase bone mass acquisition to prevent or treat diseases of skeletal fragility. Indeed, understanding the coordination of osteoblast, osteocyte and osteoclasts networks is vital to the understanding nearly all diseases of skeletal metabolism.
Funding Period: 2013-03-01 - 2018-02-28
more information: NIH RePORT

Top Publications

  1. pmc The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase Cδ cascade
    Corinne Niger
    Department of Orthopaedics, University of Maryland, School of Medicine, Baltimore, MD, USA
    J Bone Miner Res 28:1468-77. 2013
  2. pmc An intact connexin43 is required to enhance signaling and gene expression in osteoblast-like cells
    Carla Hebert
    Department of Orthopedics, University of Maryland, School of Medicine, Baltimore, Maryland, 21201
    J Cell Biochem 114:2542-50. 2013
  3. pmc Molecular mechanisms of osteoblast/osteocyte regulation by connexin43
    Joseph P Stains
    Department of Orthopaedics, University of Maryland, School of Medicine, 100 Penn Street, Allied Health Building, Room 540E, Baltimore, MD, 21201, USA
    Calcif Tissue Int 94:55-67. 2014
  4. pmc Gap junctional regulation of signal transduction in bone cells
    Atum M Buo
    Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA
    FEBS Lett 588:1315-21. 2014

Research Grants

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase Cδ cascade
    Corinne Niger
    Department of Orthopaedics, University of Maryland, School of Medicine, Baltimore, MD, USA
    J Bone Miner Res 28:1468-77. 2013
    ....
  2. pmc An intact connexin43 is required to enhance signaling and gene expression in osteoblast-like cells
    Carla Hebert
    Department of Orthopedics, University of Maryland, School of Medicine, Baltimore, Maryland, 21201
    J Cell Biochem 114:2542-50. 2013
    ..e., docking function) in order to mediate its cellular effects. Further, while the CT alone has channel independent activity, it is opposing to the effect of overexpression of the full length Cx43 channel in this cell context...
  3. pmc Molecular mechanisms of osteoblast/osteocyte regulation by connexin43
    Joseph P Stains
    Department of Orthopaedics, University of Maryland, School of Medicine, 100 Penn Street, Allied Health Building, Room 540E, Baltimore, MD, 21201, USA
    Calcif Tissue Int 94:55-67. 2014
    ..Current knowledge demonstrates that Cx43 is more than a passive channel; rather, it actively participates in the generation and modulation of cellular signals that drive skeletal development and homeostasis. ..
  4. pmc Gap junctional regulation of signal transduction in bone cells
    Atum M Buo
    Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA
    FEBS Lett 588:1315-21. 2014
    ..This review will highlight key signaling factors that have been identified as downstream effectors of Cx43 and the impact of these pathways on distinct osteoblast and osteocyte functions. ..

Research Grants30

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....