Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice

ABSTRACT We investigated whether polycystin‐1 is a bone mechanosensor. We conditionally deleted Pkd1 in mature osteoblasts/osteocytes by crossing Dmp1 ‐Cre with Pkd1 flox/m1Bei mice, in which the m1Bei allele is nonfunctional. We assessed in wild‐type and Pkd1‐ deficient mice the response to mechanical loading in vivo by ulna loading and ex vivo by measuring the response of isolated osteoblasts to fluid shear stress. We found that conditional Pkd1 heterozygotes ( Dmp1‐ Cre; Pkd1 flox/+ ) and null mice ( Pkd1 Dmp1‐cKO ) exhibited a ~40 and ~90% decrease, respectively, in functional Pkd1 transcripts in bone. Femoral bone mineral density (12 vs. 27%), trabecular bone volume (32 vs. 48%), and cortical thickness (6 vs. 17%) were reduced proportionate to the reduction of Pkd1 gene dose, as were mineral apposition rate (MAR) and expression of Runx2‐ II , Osteocalcin, Dmp1 , and Phex. Anabolic load‐induced periosteal lamellar MAR (0.58±0.14; Pkd1 Dmp1‐cKO vs. 1.68±0.34 μm/d; control) and increases in Cox‐2, c‐Jun, Wnt10b, Axin2 , and Runx2‐ II gene expression were significantly attenuated in Pkd1 Dmp1‐cKO mice compared with controls. Application of fluid shear stress to immortalized osteoblasts from Pkd1 null/null and Pkd1 m1Bei/m1Bei ‐derived osteoblasts failed to elicit the increments in cytosolic calcium observed in wild‐type controls. These data indicate that polycystin‐1 is essential for the anabolic response to skeletal loading in osteoblasts/osteocytes.—Xiao, Z., Dallas, M., Qiu, N., Nicolella, D., Cao, L., Johnson, M., Bonewald, L., Quarles, L. D. Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice. FASEB J. 25, 2418–2432 (2011). www.fasebj.org