Bone is constantly remodeled at the small scale, created by cells called osteoblasts and destroyed by cells called osteoclasts. One of the proximate causes of osteoporosis, age-related loss of bone mass and strength, is a growing imbalance between these two cell populations. Any of a range of approaches that can tilt the balance back towards osteoblasts and bone creation is likely to slow skeletal degeneration, and that is demonstrated in mice in the study linked here. As a matter of interest note that this particular approach is the exact opposite of that used in the first senolytic drugs: inhibiting cell self-destruction rather than encouraging it via the same target of Bcl2 proteins.
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 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 transgenic mice using the same promoter in order 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. Analysis revealed that the mineralizing surface was larger in trabecular bone, while the bone formation rate was increased in cortical bone. 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 due 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.