Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation

Alhashmi, Mohammad, Gremida, Abdulrahman M. E., Maharana, Santosh K., Antonaci, Marco, Kerr, Amy, Fu, Shijian, Lunn, Sharna, Turner, David A., Al-Maslamani, Noor A., Liu, Ke, Meschis, Maria M., Sutherland, Hazel, Wilson, Peter, Clegg, Peter, Wheeler, Grant N., van ‘t Hof, Robert J., Bou-Gharios, George and Yamamoto, Kazuhiro (2025) Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation. Bone Research, 13. ISSN 2095-6231

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Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip, osteoporosis and osteoarthritis. Our work addresses the critical question of how these skeletal pathologies emerge. Here, we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards, especially in the perichondrium, the stem cell layer surrounding developing limbs essential for bone formation. Lrp1 deficiency in these stem cells causes joint fusion, malformation of cartilage/bone template and markedly delayed or lack of primary ossification. These abnormalities, which resemble phenotypes associated with Wnt signalling pathways, result in severe and persistent skeletal defects including a severe deficit in hip joint and patella, and markedly deformed and low-density long bones leading to dwarfism and impaired mobility. Mechanistically, we show that LRP1 regulates core non-canonical Wnt/planar cell polarity (PCP) components that may explain the malformation of long bones. LRP1 directly binds to Wnt5a, facilitates its cell-association and endocytic degradation and recycling. In the developing limbs, LRP1 partially colocalises with Wnt5a and its deficiency alters abundance and distribution of Wnt5a and Vangl2. Finally, using Xenopus as a model system, we show the regulatory role for LRP1 in Wnt/PCP signalling. We propose that in skeletal progenitors, LRP1 plays a critical role in formation and maturity of multiple bones and joints by regulating Wnt signalling, providing novel insights into the fundamental processes of morphogenesis and the emergence of skeletal pathologies.

Item Type:	Article
Uncontrolled Keywords:	3* ,/dk/atira/pure/researchoutput/REFrank/3_
Faculty \ School:	Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Science > Research Groups > Wheeler Group Faculty of Science > Research Groups > Cells and Tissues
Depositing User:	LivePure Connector
Date Deposited:	05 Feb 2025 11:30
Last Modified:	05 Feb 2025 15:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98399
DOI:	10.1038/s41413-024-00393-x

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