The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in mice

• Published in: The Journal of clinical investigation Vol. 119; no. 10; pp. 3149 - 3159
• Main Authors: Iwasawa, Mitsuyasu, Miyazaki, Tsuyoshi, Nagase, Yuichi, Akiyama, Toru, Kadono, Yuho, Nakamura, Masaki, Oshima, Yasushi, Yasui, Tetsuro, Matsumoto, Takumi, Nakamura, Takashi, Kato, Shigeaki, Hennighausen, Lothar, Nakamura, Kozo, Tanaka, Sakae
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.10.2009
• Subjects: Animals; Apoptosis; B cells; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - metabolism; Biomedical research; Biphenyl Compounds - pharmacology; Bone and Bones - anatomy & histology; Bone and Bones - pathology; Bone marrow; Bone resorption; Bone Resorption - metabolism; Care and treatment; Cell Survival; Cells, Cultured; Development and progression; Enzyme Inhibitors - pharmacology; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Flavonoids - pharmacology; Gene expression; Genetic aspects; Genetic regulation; Kinases; Lymphoma; Lymphomas; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphology; Nitrophenols - pharmacology; Osteoclasts (Biology); Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - physiology; Physiological aspects; Piperazines - pharmacology; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteins; RANK Ligand - genetics; RANK Ligand - metabolism; Signal Transduction - physiology; src-Family Kinases; Sulfonamides - pharmacology; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci39819

The B cell lymphoma 2 (Bcl-2) family member Bcl-xL has a well-characterized antiapoptotic function in lymphoid cells. However, its functions in other cells--including osteoclasts, which are of hematopoietic origin--and other cellular processes remain unknown. Here we report an unexpected function of Bcl-xL in attenuating the bone-resorbing activity of osteoclasts in mice. To investigate the role of Bcl-xL in osteoclasts, we generated mice with osteoclast-specific conditional deletion of Bcl-x (referred to herein as Bcl-x cKO mice) by mating Bcl-xfl/fl mice with mice in which the gene encoding the Cre recombinase has been knocked into the cathepsin K locus and specifically expressed in mature osteoclasts. Although the Bcl-x cKO mice grew normally with no apparent morphological abnormalities, they developed substantial osteopenia at 1 year of age, which was caused by increased bone resorption. Bcl-x deficiency increased the bone-resorbing activity of osteoclasts despite their high susceptibility to apoptosis, whereas Bcl-xL overexpression produced the opposite effect. In addition, Bcl-x cKO osteoclasts displayed increased c-Src activity, which was linked to increased levels of vitronectin and fibronectin expression. These results suggest that Bcl-xL attenuates osteoclastic bone-resorbing activity through the decreased production of ECM proteins, such as vitronectin and fibronectin, and thus provide evidence for what we believe to be a novel cellular function of Bcl-xL.