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Protocadherin-7 contributes to maintenance of bone homeostasis through regulation of osteoclast multinucleation.

ABSTRACT: Osteoclasts are hematopoietic-derived cells that resorb bone. They are required to maintain proper bone homeostasis and skeletal strength. Although osteoclast differentiation depends on receptor activator of NF-?B ligand (RANKL) stimulation, additional molecules further contribute to osteoclast maturation. Here, we demonstrate that protocadherin-7 (Pcdh7) regulates formation of multinucleated osteoclasts and contributes to maintenance of bone homeostasis. We found that Pcdh7 expression is induced by RANKL stimulation, and that RNAi-mediated knockdown of Pcdh7 resulted in impaired formation of osteoclasts. We generated Pcdh7-deficient mice and found increased bone mass due to decreased bone resorption but without any defect in bone formation. Using an in vitro culture system, it was revealed that formation of multinucleated osteoclasts is impaired in Pcdh7-deficient cultures, while no apparent defects were observed in differentiation and function of Pcdh7-deficient osteoblasts. Taken together, these results reveal an osteoclast cell-intrinsic role for Pcdh7 in maintaining bone homeostasis. [BMB Reports 2020; 53(9): 472-477].

SUBMITTER: Kim H

PROVIDER: S-EPMC7526982 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Protocadherin-7 contributes to maintenance of bone homeostasis through regulation of osteoclast multinucleation.

Kim Hyunsoo H Takegahara Noriko N Walsh Matthew C MC Ueda Jun J Fujihara Yoshitaka Y Ikawa Masahito M Choi Yongwon Y

BMB reports 20200901 9

Osteoclasts are hematopoietic-derived cells that resorb bone. They are required to maintain proper bone homeostasis and skeletal strength. Although osteoclast differentiation depends on receptor activator of NF-κB ligand (RANKL) stimulation, additional molecules further contribute to osteoclast maturation. Here, we demonstrate that protocadherin-7 (Pcdh7) regulates formation of multinucleated osteoclasts and contributes to maintenance of bone homeostasis. We found that Pcdh7 expression is induce ...[more]

PMID: 32635982

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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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Protocadherin-7 contributes to maintenance of bone homeostasis through regulation of osteoclast multinucleation.

Publications

Protocadherin-7 contributes to maintenance of bone homeostasis through regulation of osteoclast multinucleation.

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