Conditional disruption of Pkd1 in osteoblasts results in osteopenia due to direct impairment of bone formation

Zhousheng Xiao, Shiqin Zhang, Li Cao, Ni Qiu, Valentin David, L. Darryl Quarles*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

PKD1 (polycystin-1), the disease-causing gene for ADPKD, is widely expressed in various cell types, including osteoblasts, where its function is unknown. Although global inactivation of Pkd1 in mice results in abnormal skeletal development, the presence of polycystic kidneys and perinatal lethality confound ascertaining the direct osteoblastic functions of PKD1 in adult bone. To determine the role of PKD1 in osteoblasts, we conditionally inactivated Pkd1 in postnatal mature osteoblasts by crossing Oc (osteocalcin)-Cre mice with floxed Pkd1 (Pkd1flox/m1Bei) mice to generate conditional heterozygous (Oc-Cre;Pkd1flox/+) and homozygous (Oc-Cre; Pkd1flox/m1Bei) Pkd1-deficient mice. Cre-mediated recombination (Pkd1Δflox) occurred exclusively in bone. Compared with control mice, the conditional deletion of Pkd1 from osteoblasts resulted in a gene dose-dependent reduction in bone mineral density, trabecular bone volume, and cortical thickness. In addition, mineral apposition rates and osteoblast-related gene expression, including Runx2-II (Runt-related transcription factor 2), osteocalcin, osteopontin, and bone sialoprotein, were reduced proportionate to the reduction of Pkd1 gene dose in bone of Oc-Cre;Pkd1flox/+ and Oc-Cre;Pkd1flox/m1Bei mice. Primary osteoblasts derived from Oc-Cre;Pkd1flox/m1Bei displayed impaired differentiation and suppressed activity of the phosphatidylinositdol 3-kinase-Akt-GSK3β-β-catenin signaling pathways. The conditional deletion of Pkd1 also resulted in increased adipogenesis in bone marrow and in osteoblast cultures. Thus, PKD1 directly functions in osteoblasts to regulate bone formation.

Original languageEnglish (US)
Pages (from-to)1177-1187
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number2
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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