conditional mesenchymal disruption of pkd1 results in osteopenia and polycystic kidney disease条件间充质pkd1中断导致骨量减少和多囊肾疾病.pdfVIP

Conditional Mesenchymal Disruption of Pkd1 Results in Osteopenia and Polycystic Kidney Disease Ni Qiu.¤, Zhousheng Xiao., Li Cao, Valentin David, Leigh Darryl Quarles* Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America Abstract Conditional deletion of Pkd1 in osteoblasts using either Osteocalcin(Oc)-Cre or Dmp1-Cre results in defective osteoblast- mediated postnatal bone formation and osteopenia. Pkd1 is also expressed in undifferentiated mesenchyme that gives rise to the osteoblast lineage. To examine the effects of Pkd1 on prenatal osteoblast development, we crossed Pkd1flox/flox and Col1a1(3.6)-Cre mice, which has been used to achieve selective inactivation of Pkd1 earlier in the osteoblast lineage. Control Pkd1flox/flox and Pkd1flox/+, heterozygous Col1a1(3.6)-Cre;Pkd1flox/+ and Pkd1flox/null, and homozygous Col1a1(3.6)-Cre;Pkd1flox/ flox and Col1a1(3.6)-Cre;Pkd1flox/null mice were analyzed at ages ranging from E14.5 to 8-weeks-old. Newborn Col1a1(3.6)- Cre;Pkd1flox/null mice exhibited defective skeletogenesis in association with a greater reduction in Pkd1 expression in bone. Conditional Col1a1(3.6)-Cre;Pkd1flox/+ and Col1a1(3.6)-Cre;Pkd1flox/flox mice displayed a gene dose-dependent decrease in bone formation and increase in marrow fat at 6 weeks of age. Bone marrow stromal cell and primary osteoblast cultures from homozygous Col1a1(3.6)-Cre;Pkd1flox/flox mice showed increased proliferation, impaired osteoblast development and enhanced adipogenesis ex vivo. Unexpectedly, we found evidence for Col1a1(3.6)-Cre mediated deletion of Pkd1 in extraskeletal tissues in Col1a1(3.6)-Cre;Pkd1flox/flox mice. Deletion of Pkd1 in mesenchymal precursors resulted in pancreatic and renal, but not hepatic, cyst formation. The n