Abstract
Bcl2 subfamily proteins, including Bcl2 and Bcl-XL, inhibit apoptosis. As osteoblast apoptosis is in part responsible for osteoporosis in sex steroid deficiency, glucocorticoid excess, and aging, bone loss might be inhibited by the upregulation of Bcl2; however, the effects of Bcl2 overexpression on osteoblast differentiation and bone development and maintenance have not been fully investigated. To investigate these issues, we established two lines of osteoblast-specific BCL2 transgenic mice. In BCL2 transgenic mice, bone volume was increased at 6 weeks of age but not at 10 weeks of age compared with wild-type mice. The numbers of osteoblasts and osteocytes increased, but osteoid thickness and the bone formation rate were reduced in BCL2 transgenic mice with high expression at 10 weeks of age. The number of BrdU-positive cells was increased but that of TUNEL-positive cells was unaltered at 2 and 6 weeks of age. Osteoblast differentiation was inhibited, as shown by reduced Col1a1 and osteocalcin expression. Osteoblast differentiation of calvarial cells from BCL2 transgenic mice also fell in vitro. Overexpression of BCL2 in primary osteoblasts had no effect on osteoclastogenesis in co-culture with bone marrow cells. Unexpectedly, overexpression of BCL2 in osteoblasts eventually caused osteocyte apoptosis. Osteocytes, which had a reduced number of processes, gradually died with apoptotic structural alterations and the expression of apoptosis-related molecules, and dead osteocytes accumulated in cortical bone. These findings indicate that overexpression of BCL2 in osteoblasts inhibits osteoblast differentiation, reduces osteocyte processes, and causes osteocyte apoptosis.
Highlights
Bone is a dynamic tissue that is constantly undergoing remodeling by osteoblasts and osteoclasts, and bone volume is determined by the differentiation and function of osteoblasts and osteoclasts
Bone histomorphometric analysis at 10 weeks of age showed that the numbers of osteoblasts and osteocytes were increased in both tg(L) and tg(H) compared with those in wild-type mice, but that the bone volume, osteoid thickness, and bone formation rate were not increased in tg(L) and reduced in tg(H) compared with those in wild-type mice, irrespective of the similar levels of osteoclast parameters among wild-type mice, tg(L), and tg(H) (Fig. 1J)
To investigate why alkaline phosphatase (ALP) activity was dependent on cell density, we examined the effect of BCL2 on apoptosis in vitro, because cell density is critical for osteoblast differentiation
Summary
Bone is a dynamic tissue that is constantly undergoing remodeling by osteoblasts and osteoclasts, and bone volume is determined by the differentiation and function of osteoblasts and osteoclasts. Osteoblasts, which differentiate from multipotent mesenchymal cells, express bone matrix protein genes at different levels depending on the maturity of the cells. Mesenchymal cells and preosteoblasts weakly express Col1a1, but osteoblasts show increased levels. Mature osteoblasts are embedded in the bone matrix to become osteocytes. Osteocytes located in lacunae establish an extensive intracellular and extracellular communication system via gap junction-coupled cell processes and canaliculi, through which cell processes pass throughout bone, and the communication system is extended to osteoblasts on the bone surface [1], [2]. The lacunocanalicular network formed by osteocytes is thought to be an ideal mechanosensory system and suitable for mechanotransduction, by which mechanical energy is converted into electrical and/or biochemical signals [3], [4], [5], [6], [7], [8]
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