The polycystic kidney disease 1 (Pkd1) gene is required for the responses of osteochondroprogenitor cells to midpalatal suture expansion in mice

Mechanical stress is known to modulate postnatal skeletal growth and development. However, the mechanisms underlying the mechanotransduction are not fully understood. Polycystin-1 (PC1) is a promising candidate among proteins that may play a role in the process as it has been shown to function as a flow sensor in renal epithelium and it is known to be important for skeletal development. To investigate whether PC1 is involved in mechanotransduction in skeletal tissues, mice with a conditional deficiency for PC1 in neural crest cells, osteoblasts or chondrocytes were subjected to midpalatal suture expansion. Dynamic bone labeling revealed that new bone formation in response to expansion was significantly reduced in Wnt1Cre;Pkd1 mice, as the suture area containing new bone was 14.0 ± 3.4% in mutant mice versus 65.0 ±3.8% in control mice at 2 weeks (p < 0.001). In contrast, stress-induced new bone formation was not affected in OsxCre;Pkd1 mice. The increase in cell proliferation and differentiation into osteoblasts, seen in wild-type mice 1 day after force delivery, was not observed until 14 days in Wnt1Cre;Pkd1 mice. TUNEL labeling showed a significant increase in apoptotic suture cells at days 1 and 3 (from 7.0 ± 0.5% to 13.5 ± 1.4% at day 1 and from 4.6 ± 1.1% to 10.5 ± 1.7% at day 3, p < 0.05). Abnormal ossification of nasal cartilage of Wnt1Cre;Pkd1 mice was accelerated upon suture expansion. Such ossification was also observed, but to a lesser extent in Col2a1-ER⁎Cre;Pkd1 mice. Transcript levels of Runx2 and MMP13 were significantly increased in the nasal cartilage of Wnt1Cre;Pkd1 mice compared to controls (p < 0.05 and p < 0.001, respectively), and in mutant mice with expansion versus without expansion (p < 0.05 and p < 0.001, respectively). Lack of PC1 in chondroprogenitor cells also resulted in increased cell apoptosis and an altered arrangement of chondrocytes in nasal cartilage. These results indicate that PC1 plays a critical role in the response of osteochondroprogenitor cells to the mechanical tissue stress induced by midpalatal suture expansion. They also suggest that the combination of an in vivo mechanical model, such as midpalatal suture expansion, with conditional deficiency for proteins that play a role in mechanotransduction, represents a powerful experimental strategy to explore underlying mechanisms.