Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization.
Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization.
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ENPP1缺乏破坏的遗传途径可洞悉骨质疏松症，骨质核酸的机制和矛盾的矿化。
DOI：
10.1016/j.bone.2020.115656
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发表时间：
2021-01
期刊：
影响因子：
4.1
通讯作者：
Braddock DT
中科院分区：
文献类型：
--
作者：
Maulding ND;Kavanagh D;Zimmerman K;Coppola G;Carpenter TO;Jue NK;Braddock DT
外核苷酸磷酸酶/磷酸二酯酶1（ENPP 1）缺乏可导致致死性动脉钙化（“婴儿全身动脉钙化”- GACI）、磷酸盐消耗性佝偻病（“常染色体隐性低磷酸盐血症佝偻病2型”-ARHR 2）、早发性骨质疏松症或进行性脊柱强直（"后纵韧带骨化“- OPLL）。由于ENPP 1产生强的内源性矿化抑制剂-细胞外焦磷酸盐（PPi）-ENPP 1缺乏不应导致骨量减少，因此，鉴于目前对酶功能的理解，ENPP 1相关骨质疏松症的机制并不明显。为了研究驱动ENPP 1缺乏症骨骼表型的遗传途径，我们通过RNAseq和qPCR在全骨中比较了Enpp 1asj/asj小鼠和WT同胞对的基因表达，并通过qPCR在肝脏和肾脏中比较了基因表达，将基因表达与骨微结构和生物力学表型的测量直接相关。与相关人类疾病表型相比，差异表达基因的无偏分析显示，Enpp 1asj/asj小鼠表现出骨质疏松症、ARHR 2和OPLL的强烈特征。我们发现，ENPP 1缺陷小鼠表现出减少基因转录的Wnt配体在整个骨和增加转录的可溶性Wnt抑制剂在肝脏和肾脏，提示多器官抑制Wnt活性。与骨中的Wnt抑制一致，骨中的胶原基因途径显著减少，Fgf 23显著增加，所有这些都与Enpp 1asj/asj小鼠的骨微结构缺陷和骨折风险直接相关。此外，10周龄小鼠的骨骼发现与Enpp 1转录物计数相关，但与血浆[PPi]无关，表明10周龄时的骨骼表型由催化独立的ENPP 1功能驱动。相比之下，23周Enpp 1asj/asj小鼠的骨骼发现与血浆PPi密切相关，表明长期低PPi驱动老年小鼠的骨骼表型。最后，Enpp 1和Fgf 23转录之间的相关性表明ENPP 1调节Fgf 23，我们通过给Enpp 1asj/asj小鼠施用可溶性ENPP 1-Fc并观察完整血浆FGF 23和ALP的抑制来证实。总之，我们的研究结果表明，骨质疏松症与ENPP 1缺乏症涉及抑制Wnt通过催化独立的Enpp 1途径，并验证Enpp 1asj/asj小鼠作为工具，以更好地了解OPLL和Parkinical矿化障碍。
Ectonucleotide phosphatase/phosphodiesterase 1 (ENPP1) deficiency results in either lethal arterial calcifications (‘Generalized Arterial Calcification of Infancy’ – GACI), phosphate wasting rickets (‘Autosomal Recessive Hypophosphatemic Rickets type 2’ – ARHR2), early onset osteoporosis, or progressive spinal rigidity (‘Ossification of the Posterior Longitudinal Ligament’ – OPLL). As ENPP1 generates a strong endogenous mineralization inhibitor – extracellular pyrophosphate (PPi) – ENPP1 deficiency should not result in reduced bone volume, and therefore the mechanism ENPP1 associated osteoporosis is not apparent given current understanding of the enzyme’s function. To investigate genetic pathways driving the skeletal phenotype of ENPP1 deficiency we compared gene expression in Enpp1asj/asj mice and WT sibling pairs by RNAseq and qPCR in whole bones, and in the liver and kidney by qPCR, directly correlating gene expression with measures of bone microarchitectural and biomechanical phenotypes. Unbiased analysis of the differentially expressed genes compared to relevant human disease phenotypes revealed that Enpp1asj/asj mice exhibit strong signatures of osteoporosis, ARHR2 and OPLL. We found that ENPP1 deficient mice exhibited reduced gene transcription of Wnt ligands in whole bone and increased transcription of soluble Wnt inhibitors in the liver and kidney, suggestive of multiorgan inhibition of Wnt activity. Consistent with Wnt suppression in bone, Collagen gene pathways in bone were significantly decreased and Fgf23 was significantly increased, all of which directly correlated with bone microarchitectural defects and fracture risk in Enpp1asj/asj mice. Moreover, the bone findings in 10-week old mice correlated with Enpp1 transcript counts but not plasma [PPi], suggesting that the skeletal phenotype at 10 weeks is driven by catalytically independent ENPP1 function. In contrast, the bone findings in 23-week Enpp1asj/asj mice strongly correlated with plasma PPi, suggesting that chronically low PPi drives the skeletal phenotype in older mice. Finally, correlation between Enpp1 and Fgf23 transcription suggested ENPP1 regulation of Fgf23, which we confirmed by dosing Enpp1asj/asj mice with soluble ENPP1-Fc and observing suppression of intact plasma FGF23 and ALP. In summary, our findings suggest that osteoporosis associated with ENPP1 deficiency involves the suppression of Wnt via catalytically independent Enpp1 pathways, and validates Enpp1asj/asj mice as tools to better understand OPLL and Paradoxical Mineralization Disorders.
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DOI：
10.1073/pnas.1319582110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Jansen, Robert S.;Kucukosmanoglu, Asli;van de Wetering, Koen
通讯作者：
van de Wetering, Koen
影响因子：
2.4
作者：
Kawaguchi, Yoshiharu;Kitajima, Isao;Kimura, Tomoatsu
通讯作者：
Kimura, Tomoatsu
DOI：
10.1002/jbmr.3938
发表时间：
2020-04
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Kotwal A;Ferrer A;Kumar R;Singh RJ;Murthy V;Schultz-Rogers L;Zimmermann M;Lanpher B;Zimmerman K;Stabach PR;Klee E;Braddock DT;Wermers RA
通讯作者：
Wermers RA
Wnt1通过促进ANKH表达抑制血管平滑肌细胞钙化
影响因子：
5
作者：
Chen, Beidong;Zhao, Yang;Zhao, Gexin
通讯作者：
Zhao, Gexin
影响因子：
3.9
作者：
Hoelzinger, Dominique B.;Nakada, Mitsutoshi;Berens, Michael E.
通讯作者：
Berens, Michael E.