Abstract
Mutant src(-/-) mice have osteopetrosis resulting from defective osteoclasts, the cells that resorb bone. However, signaling pathways involving Src family members in osteoclasts remain unclear. We demonstrate that expression of a truncated Src molecule, Src251, lacking the kinase domain, induces osteopetrosis in wild-type and src(+/-) mice and worsens osteopetrosis in src(-/-) mice by a novel mechanism, increased osteoclast apoptosis. Induction of apoptosis by Src251 requires a functional SH2, but not an SH3, domain and is associated with reduced AKT kinase activity. Expression of Src251 dramatically reduces osteoclast survival in response to RANKL/TRANCE/OPGL, providing evidence that Src family kinases are required in vivo for survival signaling pathways downstream from TNF family receptors.
Publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Animals
- Apoptosis
- Base Sequence
- Cell Survival
- Chickens
- DNA Primers / genetics
- Mice
- Mice, Knockout
- Mice, Transgenic
- Osteoclasts / pathology
- Osteopetrosis / genetics
- Osteopetrosis / pathology
- Protein Serine-Threonine Kinases*
- Proto-Oncogene Proteins / genetics
- Proto-Oncogene Proteins / metabolism
- Proto-Oncogene Proteins c-akt
- Receptors, Tumor Necrosis Factor / genetics*
- Receptors, Tumor Necrosis Factor / metabolism*
- Signal Transduction
- src Homology Domains
- src-Family Kinases / chemistry
- src-Family Kinases / genetics*
- src-Family Kinases / metabolism*
Substances
- DNA Primers
- Proto-Oncogene Proteins
- Receptors, Tumor Necrosis Factor
- src-Family Kinases
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins c-akt