标题：Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：37
DOI：10.1073/pnas.2203557119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing and identified likely pathogenic variants in the
LRP1 (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. We found that the timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore,
Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment.
Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic variants in the
LRP1 (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. All patients harboring the
LRP1 variants presented a typical DDH phenotype. The heterozygous
Lrp1 knockout (KO) mouse (
Lrp1
+/−) showed phenotypes recapitulating the human DDH phenotypes, indicating
Lrp1 loss of function causes DDH.
Lrp1 knockin mice with a missense variant corresponding to a human variant identified in DDH (
Lrp1
R1783W
) also presented DDH phenotypes, which were milder in heterozygotes and severer in homozygotes than those of the
Lrp1 KO mouse. The timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore,
Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mice bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant β-catenin up-regulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a β-catenin antagonist) in an shRNA-Lrp1–expressed ATDC5 cell. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment.
关键词：endevelopmental dysplasia of the hiplow-density lipoprotein receptor-related proteinautophagycartilage development
