气候变化领域集成服务门户(CCPortal): Localized chondro-ossification underlies joint dysfunction and motor deficits in the Fkbp10 mouse model of osteogenesis imperfecta

CCPortal

DOI	10.1073/pnas.2100690118
	Localized chondro-ossification underlies joint dysfunction and motor deficits in the Fkbp10 mouse model of osteogenesis imperfecta
	Lim J.; Lietman C.; Grol M.W.; Castellon A.; Dawson B.; Adeyeye M.; Rai J.; Weis M.; Keene D.R.; Schweitzer R.; Park D.; Eyre D.R.; Krakow D.; Lee B.H.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:25
英文摘要	Osteogenesis imperfecta (OI) is a genetic disorder that features wide-ranging defects in both skeletal and nonskeletal tissues. Previously, we and others reported that loss-of-function mutations in FK506 Binding Protein 10 (FKBP10) lead to skeletal deformities in conjunction with joint contractures. However, the pathogenic mechanisms underlying joint dysfunction in OI are poorly understood. In this study, we have generated a mouse model in which Fkbp10 is conditionally deleted in tendons and ligaments. Fkbp10 removal substantially reduced telopeptide lysyl hydroxylation of type I procollagen and collagen cross-linking in tendons. These biochemical alterations resulting from Fkbp10 ablation were associated with a site-specific induction of fibrosis, inflammation, and ectopic chondrogenesis followed by joint deformities in postnatal mice. We found that the ectopic chondrogenesis coincided with enhanced Gli1 expression, indicating dysregulated Hedgehog (Hh) signaling. Importantly, genetic inhibition of the Hh pathway attenuated ectopic chondrogenesis and joint deformities in Fkbp10 mutants. Furthermore, Hh inhibition restored alterations in gait parameters caused by Fkbp10 loss. Taken together, we identified a previously unappreciated role of Fkbp10 in tendons and ligaments and pathogenic mechanisms driving OI joint dysfunction. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	contracture; Fkbp10; ligament; Osteogenesis imperfecta; tendon
语种	英语
scopus关键词	fk 506 binding protein; fk 506 binding protein 10; procollagen; telopeptide; transcription factor Gli1; unclassified drug; collagen type 1; collagen type I trimeric cross-linked peptide; fk 506 binding protein; Fkbp10 protein, mouse; lysine; peptide; sonic hedgehog protein; animal cell; animal experiment; animal model; animal tissue; arthropathy; Article; biochemistry; chondrogenesis; controlled study; fibrosis; Fkbp10 gene; gait disorder; gene deletion; gene expression; hedgehog signaling; hydroxylation; in vivo study; inflammation; ligament; mouse; nonhuman; ossification; osteogenesis imperfecta; pathogenicity; perinatal period; protein cross linking; protein expression; RNA sequencing; tendon; animal; biological model; bone development; chondrocyte; complication; disease model; gait; gene expression regulation; genetics; heterotopic ossification; joint; metabolism; motor activity; newborn; osteogenesis imperfecta; pathology; pathophysiology; sequence analysis; signal transduction; Animals; Animals, Newborn; Chondrocytes; Chondrogenesis; Collagen Type I; Disease Models, Animal; Fibrosis; Gait; Gene Deletion; Gene Expression Regulation; Hedgehog Proteins; Hydroxylation; Inflammation; Joints; Ligaments; Lysine; Mice; Models, Biological; Motor Activity; Ossification, Heterotopic; Osteogenesis; Osteogenesis Imperfecta; Peptides; Sequence Analysis, RNA; Signal Transduction; Tacrolimus Binding Proteins; Tendons
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251149
作者单位	Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States; Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, United States; Research Division, Shriners Hospital for Children, Portland, OR 97239, United States; Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
推荐引用方式 GB/T 7714	Lim J.,Lietman C.,Grol M.W.,et al. Localized chondro-ossification underlies joint dysfunction and motor deficits in the Fkbp10 mouse model of osteogenesis imperfecta[J],2021,118(25).
APA	Lim J..,Lietman C..,Grol M.W..,Castellon A..,Dawson B..,...&Lee B.H..(2021).Localized chondro-ossification underlies joint dysfunction and motor deficits in the Fkbp10 mouse model of osteogenesis imperfecta.Proceedings of the National Academy of Sciences of the United States of America,118(25).
MLA	Lim J.,et al."Localized chondro-ossification underlies joint dysfunction and motor deficits in the Fkbp10 mouse model of osteogenesis imperfecta".Proceedings of the National Academy of Sciences of the United States of America 118.25(2021).