ENPP1缺陷破坏的遗传途径提供了对骨质疏松症、骨软化和反常矿化机制的深入了解,Bone

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ENPP1缺陷破坏的遗传途径提供了对骨质疏松症、骨软化和反常矿化机制的深入了解
Bone ( IF 3.5 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.bone.2020.115656
Nathan D Maulding ₁ , Dillon Kavanagh ₁ , Kristin Zimmerman ₁ , Gianfilippo Coppola ₁ , Thomas O Carpenter ₂ , Nathaniel K Jue ₃ , Demetrios T Braddock ₁

Affiliation

外核苷酸磷酸酶/磷酸二酯酶 1 (ENPP1) 缺乏会导致致命的动脉钙化（“婴儿全身性动脉钙化” - GACI）、磷酸盐消耗性佝偻病（“2 型常染色体隐性低磷性佝偻病” - ARHR2）、早发性骨质疏松症或进行性脊柱刚性（后纵韧带骨化' - OPLL）。由于 ENPP1 产生强内源性矿化抑制剂 - 细胞外焦磷酸盐 (PPi) - ENPP1 缺乏不应导致骨量减少，因此鉴于目前对该酶功能的理解，ENPP1 相关骨质疏松症的机制并不明显。为了研究驱动 ENPP1 缺陷骨骼表型的遗传途径，我们通过 RNAseq 和 qPCR 在整个骨骼中比较了 Enpp1asj/asj 小鼠和 WT 同胞对中的基因表达，并通过 qPCR 在肝脏和肾脏中比较了基因表达，直接将基因表达与骨微结构的测量相关联和生物力学表型。与相关人类疾病表型相比，差异表达基因的无偏分析表明，Enpp1asj/asj 小鼠表现出骨质疏松症、ARHR2 和 OPLL 的强烈特征。我们发现 ENPP1 缺陷小鼠表现出全骨中 Wnt 配体的基因转录减少，肝脏和肾脏中可溶性 Wnt 抑制剂的转录增加，这表明 Wnt 活性的多器官抑制。与骨骼中的 Wnt 抑制一致，骨中的胶原基因通路显着减少，Fgf23 显着增加，所有这些都与 Enpp1asj/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 Enpp1 转录物计数相关，但与血浆 [PPi] 无关，这表明 10 周龄时的骨骼表型是由催化独立的 ENPP1 功能驱动的。相比之下，23 周 Enpp1asj/asj 小鼠的骨骼发现与血浆 PPi 密切相关，这表明长期低 PPi 驱动了老年小鼠的骨骼表型。最后，Enpp1 和 Fgf23 转录之间的相关性表明 ENPP1 对 Fgf23 的遗传调控，我们通过给 Enpp1asj/asj 小鼠施用可溶性 ENPP1-Fc 并观察完整血浆 FGF23 和 ALP 的抑制来证实这一点。总之，

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Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization

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 genetic 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.

更新日期：2021-01-01

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