Skeletal conditions such as developmental dysplasia of the hip (DDH), osteoporosis and osteoarthritis affect millions worldwide, often causing chronic pain and disability. These disorders stem from complex genetic and environmental interactions that disrupt bone formation and joint development. Despite advances in treatment, effective interventions remain limited, highlighting the urgent need for research into the molecular mechanisms that govern skeletal development. Identifying critical proteins regulating the biology of these conditions could be a key step toward novel therapeutic approaches. A study published in the journal Bone Research, provides compelling new evidence of LRP1 protein essential role in bone development. Led by researchers at the University of Liverpool, the study demonstrates that LRP1 deficiency in skeletal progenitor cells leads to profound skeletal malformations.
By uncovering how LRP1 influences bone formation at the molecular level, this research offers fresh insights into the origins of skeletal disorders and potential strategies for intervention. Using a sophisticated conditional knockout mouse model, the research team explored the effects of LRP1 loss in skeletal progenitor cells. They discovered that LRP1 is highly expressed in these cells, particularly in the perichondrium (a critical layer for bone development). Mice lacking LRP1 exhibited severe skeletal abnormalities, including joint fusion, malformed cartilage templates, and delayed ossification, none of which were present in control mice. This striking contrast underscores LRP1’s indispensable role in skeletal formation. Further molecular analysis revealed that LRP1 interacts directly with Wnt5a, a key player in the non-canonical Wnt/planar cell polarity (PCP) pathway.
Liittle is known nowadays about a role of LRP1 in Wnt/PCP pathway. The markedly thicker and shorter long bones, and disrupted growth plate with disorganised columnar chondrocytes found by the research team closely resemble phenotypes associated with defects in Wnt/PCP signalling pathway. For example, deletion of core components of Wnt/PCP including Ror2, Ryk, Wnt5a and Vangl2 as well as inducible Wnt5a overexpression all resulted in shorter and thicker long bones. By facilitating Wnt5a uptake and recycling, LRP1 ensures proper Wnt signalin, an essential process for bone formation and joint integrity. This discovery not only highlights LRP1’s regulatory role in skeletal development but also establishes a direct link between Wnt signaling dysregulation and skeletal disorders. The potential applications of these data are vast.
By elucidating LRP1’s function, scientists may develop targeted treatments for conditions like osteoporosis, osteoarthritis and hip dysplasia potentially improving outcomes for millions of patients. Moreover, a deeper understanding of skeletal development could lead to preventive strategies, reducing the incidence of several bone-related disorders.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Alhashmi M, Gremida AM et al. Bone Res. 2025; 13(1):17.
Chen L et al. J Bone Miner Res. 2024; 39(12):1821-1834.
Borrell-Pages M et al. Cardiovasc Res. 2024; 120(2):140.
