Loss of the long form of Plod2 phenocopies contractures of Bruck syndrome-osteogenesis imperfecta.

Autor:	Kot A; Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States.; Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States., Chun C; Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States., Martin JH; Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States., Wachtell D; Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States., Hudson D; Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, United States., Weis M; Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, United States., Marks H; California NanoSystems Institute, University of California at Los Angeles, Los Angeles, CA 90095, United States., Srivastava S; Materials Science and Engineering, University of California at Los Angeles, Los Angeles, CA 90095, United States., Eyre DR; Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, United States., Duran I; Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States.; Laboratory of Skeletal Biomedicine, IBIMA Plataforma BIONAND and Department of Cell Biology, Genetics and Physiology, University of Málaga, Málaga, 29071, Spain., Zieba J; Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States., Krakow D; Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States.; Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States.; Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States.; Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, United States.
Jazyk:	angličtina
Zdroj:	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2024 Sep 02; Vol. 39 (9), pp. 1240-1252.
DOI:	10.1093/jbmr/zjae124
Abstrakt:	Bruck syndrome is an autosomal recessive form of osteogenesis imperfecta caused by biallelic variants in PLOD2 or FKBP10 and is characterized by joint contractures, bone fragility, short stature, and scoliosis. PLOD2 encodes LH2, which hydroxylates type I collagen telopeptide lysines, a critical step for collagen crosslinking. The Plod2 global knockout mouse model is limited by early embryonic lethality, and thus, the role of PLOD2 in skeletogenesis is not well understood. We generated a novel Plod2 mouse line modeling a variant identified in two unrelated individuals with Bruck syndrome: PLOD2 c.1559dupC, predicting a frameshift and loss of the long isoform LH2b. In the mouse, the duplication led to loss of LH2b mRNA as well as significantly reduced total LH2 protein. This model, Plod2fs/fs, survived up to E18.5 although in non-Mendelian genotype frequencies. The homozygous frameshift model recapitulated the joint contractures seen in Bruck syndrome and had indications of absent type I collagen telopeptide lysine hydroxylation in bone. Genetically labeling tendons with Scleraxis-GFP in Plod2fs/fs mice revealed the loss of extensor tendons in the forelimb by E18.5, and developmental studies showed extensor tendons developed through E14.5 but were absent starting at E16.5. Second harmonic generation showed abnormal tendon type I collagen fiber organization, suggesting structurally abnormal tendons. Characterization of the skeleton by μCT and Raman spectroscopy showed normal bone mineralization levels. This work highlights the importance of properly crosslinked type I collagen in tendon and bone, providing a promising new mouse model to further our understanding of Bruck syndrome. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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