Bone marrow monocyte PECAM-1 deficiency elicits increased osteoclastogenesis resulting in trabecular bone loss

J Immunol. 2009 Mar 1;182(5):2672-9. doi: 10.4049/jimmunol.0802398.

Abstract

In our investigations of the bone marrow (BM) of PECAM-1 null (knockout, KO) mice, we observed that the trabecular bone volume and number of trabeculae were significantly reduced in femoral and tibial long bones. Further studies in vitro revealed increased numbers and size of osteoclasts, enhanced bone resorption on dentin substrates, and hypersensitivity to macrophage CSF and receptor activator of NF-kappaB ligand in BM-derived osteoclast precursor cultures from KO mice. Associations among PECAM-1, Syk, and SHP-1 were found in wild-type BM monocyte derived osteoclast-like cells. The absence of PECAM-1 and SHP-1 interactions in the KO cells leads to the dysregulation of Syk kinases and/or phosphatases, possibly SHP-1. Indeed, KO derived osteoclast-like cells exhibited increased Syk tyrosine phosphorylation levels compared with WT cells. Lastly, WT mice engrafted with marrow from KO kindred showed loss of trabecular bone analogous to KO mice, consistent with increased osteoclastogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism
  • Aging / pathology
  • Aging / physiology
  • Animals
  • Bone Marrow Cells / enzymology
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Cells / pathology*
  • Bone Resorption / enzymology
  • Bone Resorption / metabolism*
  • Bone Resorption / pathology*
  • Cell Differentiation / genetics*
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Down-Regulation / genetics
  • Female
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Monocytes / enzymology
  • Monocytes / metabolism*
  • Monocytes / pathology
  • Osteoclasts / enzymology
  • Osteoclasts / metabolism*
  • Osteoclasts / pathology
  • Osteogenesis / genetics
  • Phosphorylation
  • Platelet Endothelial Cell Adhesion Molecule-1 / biosynthesis
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Syk Kinase
  • ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • ZAP-70 Protein-Tyrosine Kinase
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse