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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-? 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 Smad4?(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. Smad4?(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 Smad4?(Os) mice. Apoptosis in isolated calvaria cells from Smad4?(Os) mice decreased after differentiation, which was consistent with the results of the TUNEL assay and western blotting in Smad4?(Os) mice. Conversely, osteoblast cells overexpressing Smad4 showed increased apoptosis. In an apoptosis induction model of Smad4?(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.

SUBMITTER: Moon YJ

PROVIDER: S-EPMC5050296 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Smad4 controls bone homeostasis through regulation of osteoblast/osteocyte viability.

Moon Young Jae YJ Yun Chi-Young CY Choi Hwajung H Ka Sun-O SO Kim Jung Ryul JR Park Byung-Hyun BH Cho Eui-Sic ES

Experimental & molecular medicine 20160902 9

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 ...[more]

PMID: 27585718

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Project description:Osteoclast lineage commitment and differentiation have been studied extensively, although the mechanism by which transcription factor(s) control osteoclast terminal differentiation, activation, and function remains unclear. CCAAT/enhancer-binding protein ? (C/ebp?) has been reported to be a key regulator of osteoclast cell lineage commitment, yet C/ebp?'s roles in osteoclast terminal differentiation, activation and function, and bone homeostasis, under physiological or pathological conditions, have not been studied because newborn C/ebp?-null mice die within several hours after birth. Furthermore, the function of C/ebp? in osteoclast terminal differentiation, activation, and function is largely unknown. Herein, we generated and analyzed an osteoclast-specific C/ebp? conditional knockout (CKO) mouse model via Ctsk-Cre mice and found that C/ebp?-deficient mice exhibited a severe osteopetrosis phenotype due to impaired osteoclast terminal differentiation, activation, and function, including mildly reduced osteoclast number, impaired osteoclast polarization, actin formation, and bone resorption, which demonstrated the novel function of C/ebp? in cell function and terminal differentiation. Interestingly, C/ebp? deficiency did not affect bone formation or monocyte/macrophage development. Our results further demonstrated that C/ebp? deficiency suppressed the expression of osteoclast functional genes, e.g. encoding cathepsin K (Ctsk), Atp6i (Tcirg1), and osteoclast regulator genes, e.g. encoding c-fos (Fos), and nuclear factor of activated T-cells 1 (Nfatc1), while having no effect on Pu.1 (Spi1) expression. Promoter activity mapping and ChIP assay defined the critical cis-regulatory element (CCRE) in the promoter region of Nfatc1, and also showed that the CCREs were directly associated with C/ebp?, which enhanced the promoter's activity. The deficiency of C/ebp? in osteoclasts completely blocked ovariectomy-induced bone loss, indicating that C/ebp? is a promising new target for the treatment of osteolytic diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Smad4 controls bone homeostasis through regulation of osteoblast/osteocyte viability.

Publications

Smad4 controls bone homeostasis through regulation of osteoblast/osteocyte viability.

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