title: Overexpression of BCLXL in Osteoblasts Inhibits Osteoblast Apoptosis and Increases Bone Volume and Strength.
abstract: The Bcl2 family proteins, Bcl2 and BclXL, suppress apoptosis by preventing the release of caspase activators from mitochondria through the inhibition of Bax subfamily proteins. We reported that BCL2 overexpression in osteoblasts using the 2.3 kb Col1a1 promoter increased osteoblast proliferation, failed to reduce osteoblast apoptosis, inhibited osteoblast maturation, and reduced the number of osteocyte processes, leading to massive osteocyte death. We generated BCLXL (BCL2L1) transgenic mice using the same promoter to investigate BCLXL functions in bone development and maintenance. Bone mineral density in the trabecular bone of femurs was increased, whereas that in the cortical bone was similar to that in wild-type mice. Osteocyte process formation was unaffected and bone structures were similar to those in wild-type mice. A micro-CT analysis showed that trabecular bone volume in femurs and vertebrae and the cortical thickness of femurs were increased. A dynamic bone histomorphometric analysis revealed that the mineralizing surface was larger in trabecular bone, and the bone-formation rate was increased in cortical bone. Serum osteocalcin but not TRAP5b was increased, BrdU-positive osteoblastic cell numbers were increased, TUNEL-positive osteoblastic cell numbers were reduced, and osteoblast marker gene expression was enhanced in BCLXL transgenic mice. The three-point bending test indicated that femurs were stronger in BCLXL transgenic mice than in wild-type mice. The frequency of TUNEL-positive primary osteoblasts was lower in BCLXL transgenic mice than in wild-type mice during cultivation, and osteoblast differentiation was enhanced but depended on cell density, indicating that enhanced differentiation was mainly owing to reduced apoptosis. Increased trabecular and cortical bone volumes were maintained during aging in male and female mice. These results indicate that BCLXL overexpression in osteoblasts increased the trabecular and cortical bone volumes with normal structures and maintained them majorly by preventing osteoblast apoptosis, implicating BCLXL as a therapeutic target of osteoporosis. © 2016 American Society for Bone and Mineral Research.
authors: Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Takeshi
authors: T
authors: Moriishi
authors: Laboratory of Pharmacology, Hiroshima International University, Kure, Japan.
authors: Ryo
authors: R
authors: Fukuyama
authors: Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Toshihiro
authors: T
authors: Miyazaki
authors: Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Tatsuya
authors: T
authors: Furuichi
authors: Center for Diversity and Inclusion, Nagasaki University, Nagasaki, Japan.
authors: Masako
authors: M
authors: Ito
authors: Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Toshihisa
authors: T
authors: Komori
mesh_terms: D000818:Animals; D017209:Apoptosis; D015519:Bone Density; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055114:X-Ray Microtomography; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C494812:Bcl2l1 protein, mouse; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D051020:bcl-X Protein
keywords: APOPTOSIS; BCLXL; BONE FORMATION; OSTEOBLAST; TRANSGENIC MOUSE