The role of gap junctions in megakaryocyte-mediated osteoblast proliferation and differentiation

Wendy A. Ciovacco, Carolyn G. Goldberg, Amanda F. Taylor, Justin M. Lemieux, Mark C. Horowitz, Henry J. Donahue, Melissa A. Kacena

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Gap junctions (GJs) are membrane-spanning channels that facilitate intercellular communication by allowing small signaling molecules (e.g. calcium ions, inositol phosphates, and cyclic nucleotides) to pass from cell to cell. Over the past two decades, many studies have described a role for GJ intercellular communication (GJIC) in the proliferation and differentiation of many cells, including bone cells. Recently, we reported that megakaryocytes (MKs) enhance osteoblast (OB) proliferation by a juxtacrine signaling mechanism. Here we determine whether this response is facilitated by GJIC. First we demonstrate that MKs express connexin 43 (Cx43), the predominant GJ protein expressed by bone cells, including OBs. Next, we provide data showing that MKs can communicate with OBs via GJIC, and that the addition of two distinct GJ uncouplers, 18α-glycyrrhetinic acid (αGA) or oleamide, inhibits this communication. We then demonstrate that inhibiting MK-mediated GJIC further enhances the ability of MKs to stimulate OB proliferation. Finally, we show that while culturing MKs with OBs reduces gene expression of several differentiation markers/matrix proteins (type I collagen, osteocalcin, and alkaline phosphatase), reduces alkaline phosphatase enzymatic activity, and decreases mineralization in OBs, blocking GJIC does not result in MK-induced reductions in OB gene expression, enzymatic levels, or mineralized nodule formation. Overall, these data provide evidence that GJIC between MKs and OBs is functional, and that inhibiting GJIC in MK-OB cultures enhances OB proliferation without apparently altering differentiation when compared to similarly treated OB cultures. Thus, these observations regarding MK-OB GJIC inhibition may provide insight regarding potential novel targets for anabolic bone formation.

Original languageEnglish (US)
Pages (from-to)80-86
Number of pages7
JournalBone
Volume44
Issue number1
DOIs
StatePublished - Jan 1 2009

Keywords

  • Connexin 43 (Cx43)
  • GJIC
  • Megakaryocyte
  • Mouse
  • Osteoblast

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

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    Ciovacco, W. A., Goldberg, C. G., Taylor, A. F., Lemieux, J. M., Horowitz, M. C., Donahue, H. J., & Kacena, M. A. (2009). The role of gap junctions in megakaryocyte-mediated osteoblast proliferation and differentiation. Bone, 44(1), 80-86. https://doi.org/10.1016/j.bone.2008.08.117