CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development
| Autor: | Raymond P. Boot-Handford, Ella P. Dennis, Robert M. Jackson, Katarzyna A. Piróg, Michael D. Briggs, Dimitra Tsompani, Sarah M. Edwards, Anna Teti, Claire L. Hartley, Mattia Capulli, David Young |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism Endoplasmic Reticulum 03 medical and health sciences 0302 clinical medicine Chondrocytes Epidermal growth factor WNT4 Orthopedics and Sports Medicine CRELD2 Endochondral ossification Wnt Signaling Pathway WNT SIGNALING Extracellular Matrix Proteins biology Endoplasmic reticulum Wnt signaling pathway Cell Differentiation Endoplasmic Reticulum Stress LRP1 Cell biology 030104 developmental biology Chaperone (protein) biology.protein Unfolded protein response SKELETAL DEVELOPMENT Cell Adhesion Molecules |
| Zdroj: | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral ResearchReferences. 35(8) |
| ISSN: | 1523-4681 |
| Popis: | Cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) is an endoplasmic reticulum (ER)-resident chaperone highly activated under ER stress in conditions such as chondrodysplasias; however, its role in healthy skeletal development is unknown. We show for the first time that cartilage-specific deletion of Creld2 results in disrupted endochondral ossification and short limbed dwarfism, whereas deletion of Creld2 in bone results in osteopenia, with a low bone density and altered trabecular architecture. Our study provides the first evidence that CRELD2 promotes the differentiation and maturation of skeletal cells by modulating noncanonical WNT4 signaling regulated by p38 MAPK. Furthermore, we show that CRELD2 is a novel chaperone for the receptor low-density lipoprotein receptor-related protein 1 (LRP1), promoting its transport to the cell surface, and that LRP1 directly regulates WNT4 expression in chondrocytes through TGF-β1 signaling. Therefore, our data provide a novel link between an ER-resident chaperone and the essential WNT signaling pathways active during skeletal differentiation that could be applicable in other WNT-responsive tissues. © 2020 American Society for Bone and Mineral Research. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.. |
| Databáze: | OpenAIRE |
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