Monocyte-Specific Knockout of C/ebpα Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebpα in Osteoclast Differentiation and Function

Overview

Journal J Bone Miner Res

Publisher Oxford University Press

Date 2017 Nov 18

PMID 29149533

Citations 9

Authors

Wei Chen

Guochun Zhu

Joel Jules

Diep Nguyen

Yi-Ping Li

Affiliations

Soon will be listed here.

Abstract

CCAAT/enhancer-binding protein α (C/ebpα) is critical for osteoclastogenesis by regulating osteoclast (OC) lineage commitment and is also important for OC differentiation and function in vitro. However, the role of C/ebpα in postnatal skeletal development has not been reported owing to lethality in C/ebpα mice from hypoglycemia within 8 hours after birth. Herein, we generated conditional knockout mice by deleting the C/ebpα gene in monocyte via LysM-Cre to examine its role in OC differentiation and function. C/ebpα LysM-Cre mice exhibited postnatal osteopetrosis due to impaired osteoclastogenesis, OC lineage priming defects, as well as defective OC differentiation and activity. Furthermore, our ex vivo analysis demonstrated that C/ebpα conditional deletion significantly reduced OC differentiation, maturation, and activity while mildly repressing macrophage development. At the molecular level, C/ebpα deficiency significantly suppresses the expressions of OC genes associated with early stages of osteoclastogenesis as well as genes associated with OC differentiation and activity. We also identified numerous C/ebpα critical cis-regulatory elements on the Cathepsin K promoter that allow C/ebpα to significantly upregulate Cathepsin K expression during OC differentiation and activity. In pathologically induced mouse model of osteoporosis, C/ebpα deficiency can protect mice against ovariectomy-induced bone loss, uncovering a central role for C/ebpα in osteolytic diseases. Collectively, our findings have further established C/ebpα as a promising therapeutic target for bone loss by concurrently targeting OC lineage priming, differentiation, and activity. © 2017 American Society for Bone and Mineral Research.

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References

Feng R, Desbordes S, Xie H, Tillo E, Pixley F, Stanley E . PU.1 and C/EBPalpha/beta convert fibroblasts into macrophage-like cells. Proc Natl Acad Sci U S A. 2008; 105(16):6057-62. PMC: 2327209. DOI: 10.1073/pnas.0711961105. View

Ramji D, Foka P . CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J. 2002; 365(Pt 3):561-75. PMC: 1222736. DOI: 10.1042/BJ20020508. View

Ma J, Chen W, Zhang L, Tucker B, Zhu G, Sasaki H . RNA interference-mediated silencing of Atp6i prevents both periapical bone erosion and inflammation in the mouse model of endodontic disease. Infect Immun. 2012; 81(4):1021-30. PMC: 3639609. DOI: 10.1128/IAI.00756-12. View

Kurland J, Kincade P, Moore M . Regulation of B-lymphocyte clonal proliferation by stimulatory and inhibitory macrophage-derived factors. J Exp Med. 1977; 146(5):1420-35. PMC: 2180959. DOI: 10.1084/jem.146.5.1420. View

Wu M, Chen W, Lu Y, Zhu G, Hao L, Li Y . Gα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway. Nat Commun. 2017; 8:13700. PMC: 5253683. DOI: 10.1038/ncomms13700. View

Friedman A . C/EBPalpha induces PU.1 and interacts with AP-1 and NF-kappaB to regulate myeloid development. Blood Cells Mol Dis. 2007; 39(3):340-3. PMC: 2083642. DOI: 10.1016/j.bcmd.2007.06.010. View

Kelly K, Tanaka S, Baron R, Gimble J . Murine bone marrow stromally derived BMS2 adipocytes support differentiation and function of osteoclast-like cells in vitro. Endocrinology. 1998; 139(4):2092-101. DOI: 10.1210/endo.139.4.5915. View

Clausen B, Burkhardt C, Reith W, Renkawitz R, Forster I . Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 2000; 8(4):265-77. DOI: 10.1023/a:1008942828960. View

Growney J, Shigematsu H, Li Z, Lee B, Adelsperger J, Rowan R . Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood. 2005; 106(2):494-504. PMC: 1895175. DOI: 10.1182/blood-2004-08-3280. View

10.

Asagiri M, Takayanagi H . The molecular understanding of osteoclast differentiation. Bone. 2006; 40(2):251-64. DOI: 10.1016/j.bone.2006.09.023. View

11.

Chen W, Yang S, Abe Y, Li M, Wang Y, Shao J . Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence. Hum Mol Genet. 2007; 16(4):410-23. PMC: 3578583. DOI: 10.1093/hmg/ddl474. View

12.

Chen W, Li Y . Generation of mouse osteoclastogenic cell lines immortalized with SV40 large T antigen. J Bone Miner Res. 1998; 13(7):1112-23. DOI: 10.1359/jbmr.1998.13.7.1112. View

13.

Di Stefano B, Collombet S, Jakobsen J, Wierer M, Sardina J, Lackner A . C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4. Nat Cell Biol. 2016; 18(4):371-81. DOI: 10.1038/ncb3326. View

14.

Zhao H, Ito Y, Chappel J, Andrews N, Teitelbaum S, Ross F . Synaptotagmin VII regulates bone remodeling by modulating osteoclast and osteoblast secretion. Dev Cell. 2008; 14(6):914-25. PMC: 2480494. DOI: 10.1016/j.devcel.2008.03.022. View

15.

Boyle W, Simonet W, Lacey D . Osteoclast differentiation and activation. Nature. 2003; 423(6937):337-42. DOI: 10.1038/nature01658. View

16.

Zhang Y, Wang L, Song Y, Zhao X, Wong M, Zhang W . Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice. Osteoporos Int. 2015; 27(3):1083-1092. DOI: 10.1007/s00198-015-3348-y. View

17.

Yang S, Li Y . RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca2+]i oscillation regulation. Genes Dev. 2007; 21(14):1803-16. PMC: 1920174. DOI: 10.1101/gad.1544107. View

18.

Friedman A . C/EBPα in normal and malignant myelopoiesis. Int J Hematol. 2015; 101(4):330-41. PMC: 4696001. DOI: 10.1007/s12185-015-1764-6. View

19.

Welner R, Bararia D, Amabile G, Czibere A, Benoukraf T, Bach C . C/EBPα is required for development of dendritic cell progenitors. Blood. 2013; 121(20):4073-81. PMC: 3656447. DOI: 10.1182/blood-2012-10-463448. View

20.

Feng S, Deng L, Chen W, Shao J, Xu G, Li Y . Atp6v1c1 is an essential component of the osteoclast proton pump and in F-actin ring formation in osteoclasts. Biochem J. 2008; 417(1):195-203. PMC: 2773039. DOI: 10.1042/BJ20081073. View