Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation
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 s...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00393-x |
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| author | Mohammad Alhashmi Abdulrahman M. E. Gremida Santosh K. Maharana Marco Antonaci Amy Kerr Shijian Fu Sharna Lunn David A. Turner Noor A. Al-Maslamani Ke Liu Maria M. Meschis Hazel Sutherland Peter Wilson Peter Clegg Grant N. Wheeler Robert J. van ‘t Hof George Bou-Gharios Kazuhiro Yamamoto |
| author_facet | Mohammad Alhashmi Abdulrahman M. E. Gremida Santosh K. Maharana Marco Antonaci Amy Kerr Shijian Fu Sharna Lunn David A. Turner Noor A. Al-Maslamani Ke Liu Maria M. Meschis Hazel Sutherland Peter Wilson Peter Clegg Grant N. Wheeler Robert J. van ‘t Hof George Bou-Gharios Kazuhiro Yamamoto |
| author_sort | Mohammad Alhashmi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2259694d1ffe43dfad518550b97013a1 |
| institution | Kabale University |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-2259694d1ffe43dfad518550b97013a12025-01-26T12:19:45ZengNature Publishing GroupBone Research2095-62312025-01-0113111710.1038/s41413-024-00393-xSkeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulationMohammad Alhashmi0Abdulrahman M. E. Gremida1Santosh K. Maharana2Marco Antonaci3Amy Kerr4Shijian Fu5Sharna Lunn6David A. Turner7Noor A. Al-Maslamani8Ke Liu9Maria M. Meschis10Hazel Sutherland11Peter Wilson12Peter Clegg13Grant N. Wheeler14Robert J. van ‘t Hof15George Bou-Gharios16Kazuhiro Yamamoto17Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolSchool of Biological Sciences, University of East Anglia, Norwich Research ParkSchool of Biological Sciences, University of East Anglia, Norwich Research ParkSchool of Biological Sciences, University of East Anglia, Norwich Research ParkInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolSchool of Biological Sciences, University of East Anglia, Norwich Research ParkInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolInstitute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of LiverpoolAbstract 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.https://doi.org/10.1038/s41413-024-00393-x |
| spellingShingle | Mohammad Alhashmi Abdulrahman M. E. Gremida Santosh K. Maharana Marco Antonaci Amy Kerr Shijian Fu Sharna Lunn David A. Turner Noor A. Al-Maslamani Ke Liu Maria M. Meschis Hazel Sutherland Peter Wilson Peter Clegg Grant N. Wheeler Robert J. van ‘t Hof George Bou-Gharios Kazuhiro Yamamoto Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation Bone Research |
| title | Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation |
| title_full | Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation |
| title_fullStr | Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation |
| title_full_unstemmed | Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation |
| title_short | Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation |
| title_sort | skeletal progenitor lrp1 deficiency causes severe and persistent skeletal defects with wnt pathway dysregulation |
| url | https://doi.org/10.1038/s41413-024-00393-x |
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