Loss of Cbl-b Increases Osteoclast Bone-Resorbing Activity and Induces Osteopenia

Autor: Cecile Itzsteink, Arata Nakajima, Lynn Neff, Naga Suresh Adapala, Riccardo Chiusaroli, Roland Baron, William C. Horne, Archana Sanjay
Rok vydání: 2009
Předmět:
medicine.medical_specialty
Endocrinology
Diabetes and Metabolism
Cellular differentiation
p38 mitogen-activated protein kinases
Osteoclasts
Biology
p38 Mitogen-Activated Protein Kinases
Bone resorption
Mice
Cell Movement
Osteoclast
hemic and lymphatic diseases
Internal medicine
medicine
Animals
Orthopedics and Sports Medicine
Proto-Oncogene Proteins c-cbl
Bone Resorption
Adaptor Proteins
Signal Transducing
Mice
Knockout
Bone Development
Kinase
RANK Ligand
fungi
NF-kappa B
Signal transducing adaptor protein
Cell Differentiation
Original Articles
Embryo
Mammalian
Protein Structure
Tertiary
Cell biology
Bone Diseases
Metabolic
enzymes and coenzymes (carbohydrates)
medicine.anatomical_structure
Endocrinology
biological phenomena
cell phenomena
and immunity
Signal transduction
Tyrosine kinase
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
Zdroj: Journal of Bone and Mineral Research. 24:1162-1172
ISSN: 0884-0431
DOI: 10.1359/jbmr.090205
Popis: Cbl proteins are multifunctional adaptor molecules that modulate cellular activity by targeting the ubiquitylating system, endocytic complexes, and other effectors to a wide variety of regulatory proteins, especially activated receptor and nonreceptor tyrosine kinases. Cbl and Cbl-b perform unique functions in various cells, in addition to redundant functions that are required for embryonic development. We previously showed that eliminating Cbl impaired osteoclast motility, which modestly delayed embryonic bone development. We now report that Cbl-b(-/-) mice are osteopenic, because of increased bone resorption with little compensating increase in bone formation. In vitro bone-resorbing activity and differentiation of osteoclast-like cells (OCLs) were increased, as were some RANKL-induced signaling events (activation of NF-kappaB and the mitogen-activated protein kinases extracellular signal-regulated kinase [ERK] and p38), suggesting that specific RANKL-activated mechanisms contribute to the increased rate of differentiation and bone-resorbing activity. Re-expressing Cbl-b in Cbl-b(-/-) OCLs normalized the increased bone-resorbing activity and overexpressing Cbl-b in wildtype OCLs inhibited bone resorption. Cbl was without effect in either wildtype or Cbl-b(-/-) OCLs. Functional tyrosine kinase binding (TKB) and RING finger domains were required for the rescue by Cbl-b. Thus, both Cbl and Cbl-b perform regulatory functions in osteoclasts that are unique to one or the other protein (i.e., functions that cannot be compensated by the other homolog). One of Cbl-b's unique functions in osteoclasts is to downregulate bone resorption.
Databáze: OpenAIRE
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