Bone marrow monocyte PECAM-1 deficiency elicits increased osteoclastogenesis resulting in trabecular bone loss.
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.
Wu
Yue
Y
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Tworkoski
Kathryn
K
Michaud
Michael
M
Madri
Joseph A
JA
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D001862:Bone Resorption / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse