title: Smad4 controls bone homeostasis through regulation of osteoblast/osteocyte viability.
abstract: Regulation of osteoblast and osteocyte viability is essential for bone homeostasis. Smad4, a major transducer of bone morphogenetic protein and transforming growth factor-β signaling pathways, regulates apoptosis in various cell types through a mitochondrial pathway. However, it remains poorly understood whether Smad4 is necessary for the regulation of osteoblast and osteocyte viability. In this study, we analyzed Smad4Δ(Os) mice, in which Smad4 was subjected to tissue-specific disruption under the control of the 2.3-kb Col1a1 promoter, to understand the functional significance of Smad4 in regulating osteoblast/osteocyte viability during bone formation and remodeling. Smad4Δ(Os) mice showed a significant increase in osteoblast number and osteocyte density in the trabecular and cortical regions of the femur, whereas osteoclast activity was significantly decreased. The proliferation of osteoblasts/osteocytes did not alter, as shown by measuring 5'-bromo-2'deoxyuridine incorporation. By contrast, the percentage of TUNEL-positive cells decreased, together with a decrease in the Bax/Bcl-2 ratio and in the proteolytic cleavage of caspase 3, in Smad4Δ(Os) mice. Apoptosis in isolated calvaria cells from Smad4Δ(Os) mice decreased after differentiation, which was consistent with the results of the TUNEL assay and western blotting in Smad4Δ(Os) mice. Conversely, osteoblast cells overexpressing Smad4 showed increased apoptosis. In an apoptosis induction model of Smad4Δ(Os) mice, osteoblasts/osteocytes were more resistant to apoptosis than were control cells, and, consequently, bone remodeling was attenuated. These findings indicate that Smad4 has a significant role in regulating osteoblast/osteocyte viability and therefore controls bone homeostasis.
authors: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.|Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Chonbuk National University School of Dentistry, Jeonju, Jeonbuk, Republic of Korea.
authors: Young Jae
authors: YJ
authors: Moon
authors: Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Chonbuk National University School of Dentistry, Jeonju, Jeonbuk, Republic of Korea.
authors: Chi-Young
authors: CY
authors: Yun
authors: Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Chonbuk National University School of Dentistry, Jeonju, Jeonbuk, Republic of Korea.
authors: Hwajung
authors: H
authors: Choi
authors: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.
authors: Sun-O
authors: SO
authors: Ka
authors: Department of Orthopaedic Surgery, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.|Research Institute of Clinical Medicine, Chonbuk National University Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors: Jung Ryul
authors: JR
authors: Kim
authors: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.
authors: Byung-Hyun
authors: BH
authors: Park
authors: Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Chonbuk National University School of Dentistry, Jeonju, Jeonbuk, Republic of Korea.
authors: Eui-Sic
authors: ES
authors: Cho
mesh_terms: D000818:Animals; D017209:Apoptosis; D001862:Bone Resorption / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D006706:Homeostasis; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D051901:Smad4 Protein / Q000378:metabolism*
chemical_list: D051901:Smad4 Protein; C490810:Smad4 protein, mouse