Abstract
Introduction: B-cell leukemia/lymphoma 2 (Bcl2) is a proto-oncogene best known for its ability to suppress cell death. However, the role of Bcl2 in the skeletal system is unknown. Bcl2, has been hypothesized to play an important anti-apoptotic role in osteoblasts during anabolic actions of PTH. Although rational, this has not been validated in vivo; hence, the impact of Bcl2 in bone remains unknown. Materials and Methods: The bone phenotype of Bcl2 homozygous mutant (Bcl2-/-) mice was analyzed with histomorphometry and μCT. Calvarial osteoblasts were isolated and evaluated for their cellular activity. Osteoclastogenesis was induced from bone marrow cells using RANKL and macrophage-colony stimulating factor (M-CSF), and their differentiation was analyzed. PTH(1-34) (50 μg/kg) or vehicle was administered daily to Bcl2 +/+ and Bcl2-/- mice (4 days old) for 9 days to clarify the influence of Bcl2 ablation on PTH anabolic actions. Western blotting and real-time PCR were performed to detect Bcl2 expression in calvarial osteoblasts in response to PTH ex vivo. Results: There were reduced numbers of osteoclasts in Bcl2-/- mice, with a resultant increase in bone mass. Bcl2 -/- bone marrow-derived osteoclasts ex vivo were significantly larger in size and short-lived compared with wildtype, suggesting a pro-apoptotic nature of Bcl2-/- osteoclasts. In contrast, osteoblasts were entirely normal in their proliferation, differentiation, and mineralization. Intermittent administration of PTH increased bone mass similarly in Bcl2 +/+ and Bcl2-/- mice. Finally, Western blotting and real-time PCR showed that Bcl2 levels were not induced in response to PTH in calvarial osteoblasts. Conclusions: Bcl2 is critical in osteoclasts but not osteoblasts. Osteoclast suppression is at least in part responsible for increased bone mass of Bcl2-/- mice, and Bcl2 is dispensable in PTH anabolic actions during bone growth.
Original language | English (US) |
---|---|
Pages (from-to) | 621-632 |
Number of pages | 12 |
Journal | Journal of Bone and Mineral Research |
Volume | 23 |
Issue number | 5 |
DOIs | |
State | Published - May 2008 |
Externally published | Yes |
Keywords
- Anabolic
- B-cell leukemia/lymphoma 2
- Osteoblasts
- Osteoclasts
- PTH
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Orthopedics and Sports Medicine