Multi-omics analyses reveal aberrant differentiation trajectory with WNT1 loss-of-function in type XV osteogenesis imperfecta.

Autor:	Tan Z; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China.; Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Chen P; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China.; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; The AI and Big Data Lab, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China., Zhang J; Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China., Shek HT; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China., Li Z; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China., Zhou X; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China., Zhou Y; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China., Yin S; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China., Dong L; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China., Feng L; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China., Wong JSH; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China.; Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Gao B; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China.; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China., To MKT; Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.; Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China.; Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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. 1253-1267.
DOI:	10.1093/jbmr/zjae123
Abstrakt:	Osteogenesis imperfecta (OI) is a group of severe genetic bone disorders characterized by congenital low bone mass, deformity, and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 variants. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 variants and found that the proportion of type XV patients was around 10.3% (25 out of 243) with a diverse spectrum of phenotypes. Functional assays indicated that variants of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure, and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST (sclerostin) was dramatically reduced in type XV patients compared to patients with COL1A1 quantitative variants. Single-cell transcriptome data generated from human tibia samples of patients diagnosed with type XV OI and leg-length discrepancy, respectively, revealed aberrant differentiation trajectories of skeletal progenitors and impaired maturation of osteocytes with loss of WNT1, resulting in excessive CXCL12+ progenitors, fewer mature osteocytes, and the existence of abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV OI and relative low bone mass diseases such as early onset osteoporosis. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
Databáze:	MEDLINE
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