title: Loss of Cbl-PI3K interaction in mice prevents significant bone loss following ovariectomy.
abstract: Cbl and Cbl-b are E3 ubiquitin ligases and adaptor proteins, which perform regulatory roles in bone remodeling. Cbl-/- mice have delayed bone development due to decreased osteoclast migration. Cbl-b-/- mice are osteopenic due to increased bone resorbing activity of osteoclasts. Unique to Cbl, but not present in Cbl-b, is tyrosine 737 in the YEAM motif, which upon phosphorylation provides a binding site for the regulatory p85 subunit of PI3K. Substitution of tyrosine 737 with phenylalanine (Y737F, CblYF/YF mice) prevents Y737 phosphorylation and abrogates the Cbl-PI3K interaction. We have previously reported that CblYF/YF mice had increased bone volume due to defective bone resorption and increased bone formation. Here we show that the lumbar vertebra from CblYF/YF mice did not have significant bone loss following ovariectomy. Our data also suggests that abrogation of Cbl-PI3K interaction in mice results in the loss of coupling between bone resorption and formation, since ovariectomized CblYF/YF mice did not show significant changes in serum levels of c-terminal telopeptide (CTX), whereas the serum levels of pro-collagen type-1 amino-terminal pro-peptide (P1NP) were decreased. In contrast, following ovariectomy, Cbl-/- and Cbl-b-/- mice showed significant bone loss in the tibiae and L2 vertebrae, concomitant with increased serum CTX and P1NP levels. These data indicate that while lack of Cbl or Cbl-b distinctly affects bone remodeling, only the loss of Cbl-PI3K interaction protects mice from significant bone loss following ovariectomy.
authors.affiliation: Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Naga Suresh
authors.initials: NS
authors.lastname: Adapala
authors.affiliation: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Holland
authors.affiliation: Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Scanlon
authors.affiliation: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Barbe
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley 6009, Australia.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Tsygankov
authors.affiliation: Department of Medicine, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Lorenzo
authors.affiliation: Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT 06032, USA. Electronic address: asanjay@uchc.edu.
authors.forename: Archana
authors.initials: A
authors.lastname: Sanjay
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000097:blood; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D010052:Ovariectomy; D010455:Peptides / Q000097:blood; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases
keywords: Bone resorption; Cbl; Cbl-b; Osteoclast; Ovariectomy; PI3K