title: Osteoblast-specific deletion of Hrpt2/Cdc73 results in high bone mass and increased bone turnover.
abstract: 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;Cdc73flox/floxbones displayed large cortical pores actively undergoing bone remodeling. Additionally the cortical bone of OCN-Cre;Cdc73flox/floxfemurs contained osteocytes with marked amounts of cytoplasmic RNA and a high rate of apoptosis. Transcriptional analysis via RNA-seq within OCN-Cre;Cdc73flox/floxosteoblasts 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.
authors.affiliation: 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.
authors.forename: Casey J
authors.initials: CJ
authors.lastname: Droscha
authors.affiliation: 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.
authors.forename: Cassandra R
authors.initials: CR
authors.lastname: Diegel
authors.affiliation: 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.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Ethen
authors.affiliation: 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.
authors.forename: Travis A
authors.initials: TA
authors.lastname: Burgers
authors.affiliation: 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.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: McDonald
authors.affiliation: 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.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Maupin
authors.affiliation: 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.
authors.forename: Agni S
authors.initials: AS
authors.lastname: Naidu
authors.affiliation: OB/GYN Department, Bronx-Lebanon Hospital Center, Bronx, NY, USA.
authors.forename: PengFei
authors.initials: P
authors.lastname: Wang
authors.affiliation: National Cancer Center of Singapore and SingHealth Duke-NUS Institute of Precision Medicine, Singapore.
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.affiliation: 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.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: C529591:HRPT2 protein, mouse; D025521:Tumor Suppressor Proteins
keywords: Cdc73; Hrpt2; Osteocyte apoptosis; PAF1 complex; Parafibromin