FLNA- filaminopathy skeletal phenotypes are not due to an osteoblast autonomous loss-of-function.

Autor:	Wade EM; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Goodin EA; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Wang Y; Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada., Morgan T; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Callon KE; Bone and Joint Research Group, Department of Medicine, School of Medicine, The University of Auckland, Auckland, New Zealand., Watson M; Bone and Joint Research Group, Department of Medicine, School of Medicine, The University of Auckland, Auckland, New Zealand., Daniel PB; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Cornish J; Bone and Joint Research Group, Department of Medicine, School of Medicine, The University of Auckland, Auckland, New Zealand., McCulloch CA; Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada., Robertson SP; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Jazyk:	angličtina
Zdroj:	Bone reports [Bone Rep] 2023 Feb 28; Vol. 18, pp. 101668. Date of Electronic Publication: 2023 Feb 28 (Print Publication: 2023).
DOI:	10.1016/j.bonr.2023.101668
Abstrakt:	Mutations in FLNA , which encodes the cytoskeletal protein FLNA, cause a spectrum of sclerosing skeletal dysplasias. Although many of these genetic variants are recurrent and cluster within the gene, the pathogenic mechanism that underpins the development of these skeletal phenotypes is unknown. To determine if the skeletal dysplasia in FLNA -related conditions is due to a cell-autonomous loss-of-function localising to osteoblasts and/or osteocytes, we utilised mouse models to conditionally remove Flna from this cellular lineage. Flna was conditionally knocked out from mature osteocytes using the Dmp1- promoter driven Cre-recombinase expressing mouse, as well as the committed osteoblast lineage using the Osx- Cre or Col1a1 -Cre expressing lines. We measured skeletal parameters with μCT and histological methods, as well as gene expression in the mineralised skeleton. We found no measureable differences between the conditional Flna knockout mice, and their control littermate counterparts. Moreover, all of the conditional Flna knockout mice, developed and aged normally. From this we concluded that the skeletal dysplasia phenotype associated with pathogenic variants in FLNA is not caused by a cell-autonomous loss-of-function in the osteoblast-osteocyte lineage, adding more evidence to the hypothesis that these phenotypes are due to gain-of-function in FLNA. Competing Interests: The authors have no conflicts of interest to declare. (Crown Copyright © 2023 Published by Elsevier Inc.)
Databáze:	MEDLINE
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