Osteoblast-specific deletion of Hrpt2/Cdc73 results in high bone mass and increased bone turnover.

Autor: Droscha CJ; Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA., Diegel CR; Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA., Ethen NJ; Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA., Burgers TA; Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA., McDonald MJ; Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA., Maupin KA; Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA., Naidu AS; Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA., Wang P; OB/GYN Department, Bronx-Lebanon Hospital Center, Bronx, NY, USA., Teh BT; National Cancer Center of Singapore and SingHealth Duke-NUS Institute of Precision Medicine, Singapore., Williams BO; Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA. Electronic address: bart.williams@vai.org.
Jazyk: angličtina
Zdroj: Bone [Bone] 2017 May; Vol. 98, pp. 68-78. Date of Electronic Publication: 2017 Apr 03.
DOI: 10.1016/j.bone.2016.12.006
Abstrakt: Inactivating mutations that lead to loss of heterozygosity within the HRPT2/Cdc73 gene are directly linked to the development of primary hyperparathyroidism, parathyroid adenomas, and ossifying fibromas of the jaw (HPT-JT). The protein product of the Cdc73 gene, parafibromin, is a core member of the polymerase-associated factors (PAF) complex, which coordinates epigenetic modifiers and transcriptional machinery to control gene expression. We conditionally deleted Cdc73 within mesenchymal progenitors or within mature osteoblasts and osteocytes to determine the consequences of parafibromin loss within the mesenchymal lineage. Homozygous deletion of Cdc73 via the Dermo1-Cre driver resulted in embryos which lacked mesenchymal organ development of internal organs, including the heart and fetal liver. Immunohistochemical detection of cleaved caspase-3 revealed extensive apoptosis within the progenitor pools of developing organs. Unexpectedly, when Cdc73 was homozygously deleted within mature osteoblasts and osteocytes (via the Ocn-Cre driver), the mice had a normal life span but increased cortical and trabecular bone. OCN-Cre;Cdc73 flox/flox bones displayed large cortical pores actively undergoing bone remodeling. Additionally the cortical bone of OCN-Cre;Cdc73 flox/flox femurs contained osteocytes with marked amounts of cytoplasmic RNA and a high rate of apoptosis. Transcriptional analysis via RNA-seq within OCN-Cre;Cdc73 flox/flox osteoblasts showed that loss of Cdc73 led to a derepression of osteoblast-specific genes, specifically those for collagen and other bone matrix proteins. These results aid in our understanding of the role parafibromin plays within transcriptional regulation, terminal differentiation, and bone homeostasis.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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