Mechanical loading is required for bone homeostasis,but the underlying mechanism is still unclear.Our previous studies revealed that the mechanical protein polycystin-1(PC1,encoded by Pkd1)is critical for bone formati...Mechanical loading is required for bone homeostasis,but the underlying mechanism is still unclear.Our previous studies revealed that the mechanical protein polycystin-1(PC1,encoded by Pkd1)is critical for bone formation.However,the role of PC1 in bone resorption is unknown.Here,we found that PC1directly regulates osteoclastogenesis and bone resorption.The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts,decreased bone resorption,and increased bone mass.A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease,which is mainly caused by loss-of-function mutation of the PKD1 gene,is associated with a lower risk of hip fracture than those with other chronic kidney diseases.Moreover,mice with osteoclastspecific knockout of Pkd1 showed complete resistance to unloading-induced bone loss.A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass.Pharmacological regulation of the PC1-TAZ axis alleviated unloading-and estrogen deficiency-induced bone loss.Thus,the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.展开更多
基金supported by the National Key Research and Development Program of China(2019YFA0111900,2022YFC3601900 and 2022YFC2505500)the National Natural Science Foundation of China(82261160397,82272560,81922017,92149306 and 82120108009)+5 种基金the NSFC/RGC Joint Research Schemethe Research Grants Council(UGC)of the Hong Kong Special Administrative Region and the National Natural Science Foundation of China(N_CUHK483/22)the Center for Neuromusculoskeletal Restorative Medicine by Innovation and Technology Commission(ITC)of Hong Kong SAR,China(CNRM at Inno HK),the National Institutes of Health(R61-AR073518 and R01-AR071930)the Key Research and Development Program of Hunan Province(2022SK2023)the Science and Technology Innovation Program of Hunan Province(2023RC1027,2022RC1009 and 2022RC3075)the Hunan Provincial Science and Technology Department(2023JJ30896)。
文摘Mechanical loading is required for bone homeostasis,but the underlying mechanism is still unclear.Our previous studies revealed that the mechanical protein polycystin-1(PC1,encoded by Pkd1)is critical for bone formation.However,the role of PC1 in bone resorption is unknown.Here,we found that PC1directly regulates osteoclastogenesis and bone resorption.The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts,decreased bone resorption,and increased bone mass.A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease,which is mainly caused by loss-of-function mutation of the PKD1 gene,is associated with a lower risk of hip fracture than those with other chronic kidney diseases.Moreover,mice with osteoclastspecific knockout of Pkd1 showed complete resistance to unloading-induced bone loss.A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass.Pharmacological regulation of the PC1-TAZ axis alleviated unloading-and estrogen deficiency-induced bone loss.Thus,the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.
