Osteoblast-specific deletion of Pkd2 leads to low-turnover osteopenia and reduced bone marrow adiposity.
Osteoblast-specific deletion of Pkd2 leads to low-turnover osteopenia and reduced bone marrow adiposity.
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DOI：
10.1371/journal.pone.0114198
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Quarles LD
中科院分区：
文献类型：
--
作者：
Xiao Z;Cao L;Liang Y;Huang J;Stern AR;Dallas M;Johnson M;Quarles LD
多囊蛋白-1 （Pkd1）与多囊蛋白-2 （Pkd2）相互作用形成相互依赖的信号复合物。成骨细胞谱系中Pkd1的选择性缺失相互调节成骨细胞发生和脂肪形成。Pkd2在骨骼发育中的作用尚未明确。为此，我们通过交叉骨钙素(Oc)-Cre，使成熟成骨细胞中的Pkd2条件失活；Pkd2 +/空小鼠与floxed Pkd2 （Pkd2 flox/flox）小鼠。Oc-Cre;Pkd2 flox/null （Pkd2 Oc-cKO）小鼠的骨矿物质密度、骨小梁体积、皮质厚度、矿物质附着率降低，骨的生物力学性能受损。Pkd2缺乏导致runt相关转录因子2 （Runx2）在骨中的表达减少，体外成骨细胞分化受损。骨钙素、骨桥蛋白、骨涎蛋白（Bsp）、与X染色体内肽酶同源的磷酸盐调节基因（Phex）、牙本质基质蛋白1 （Dmp1）、硬化蛋白（Sost）和成纤维细胞生长因子23 （FGF23）等成骨相关基因的表达与occ - cre骨中Pkd2基因剂量的减少成比例降低；Pkd2 flox/+和c- cre；Pkd2 flox/null小鼠。Pkd2的缺失还导致过氧化物酶体增殖物激活受体γ (PPARγ)表达减少，体内骨髓脂肪减少，体外成骨细胞培养脂肪生成减少。具有pdz结合基序的转录共激活因子（TAZ）和yes相关蛋白（YAP）相互作用于Runx2和PPARγ的共激活因子和共抑制因子，在Oc-Cre骨中减少；Pkd2 flox/null小鼠。因此，Pkd1和Pkd2在成骨细胞分化中具有协同作用，而在脂肪形成中具有相反的作用，这表明Pkd1和Pkd2信号通路可以独立影响骨的间充质谱系。
Polycystin-1 (Pkd1) interacts with polycystin-2 (Pkd2) to form an interdependent signaling complex. Selective deletion of Pkd1 in the osteoblast lineage reciprocally regulates osteoblastogenesis and adipogenesis. The role of Pkd2 in skeletal development has not been defined. To this end, we conditionally inactivated Pkd2 in mature osteoblasts by crossing Osteocalcin (Oc)-Cre;Pkd2 +/null mice with floxed Pkd2 (Pkd2 flox/flox) mice. Oc-Cre;Pkd2 flox/null (Pkd2 Oc-cKO) mice exhibited decreased bone mineral density, trabecular bone volume, cortical thickness, mineral apposition rate and impaired biomechanical properties of bone. Pkd2 deficiency resulted in diminished Runt-related transcription factor 2 (Runx2) expressions in bone and impaired osteoblastic differentiation ex vivo. Expression of osteoblast-related genes, including, Osteocalcin, Osteopontin, Bone sialoprotein (Bsp), Phosphate-regulating gene with homologies to endopeptidases on the X chromosome (Phex), Dentin matrix protein 1 (Dmp1), Sclerostin (Sost), and Fibroblast growth factor 23 (FGF23) were reduced proportionate to the reduction of Pkd2 gene dose in bone of Oc-Cre;Pkd2 flox/+ and Oc-Cre;Pkd2 flox/null mice. Loss of Pkd2 also resulted in diminished peroxisome proliferator-activated receptor γ (PPARγ) expression and reduced bone marrow fat in vivo and reduced adipogenesis in osteoblast culture ex vivo. Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP), reciprocally acting as co-activators and co-repressors of Runx2 and PPARγ, were decreased in bone of Oc-Cre;Pkd2 flox/null mice. Thus, Pkd1 and Pkd2 have coordinate effects on osteoblast differentiation and opposite effects on adipogenesis, suggesting that Pkd1 and Pkd2 signaling pathways can have independent effects on mesenchymal lineage commitment in bone.
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