LRP3, a member of the low-density lipoprotein receptor (LDLR) family, encodes a 770-amino-acid type 1 membrane protein. It is involved in multiple biological processes such as extracellular matrix metabolism in chondrocytes, and may be associated with pathways like the Ras signaling pathway. LRP3 is expressed in a wide range of human tissues, with high expression in skeletal muscle and ovary [4].

In osteoarthritis, Lrp3 knockout (KO) mouse models and in vitro experiments with LRP3-lentiviral-transduced chondrocytes show that LRP3 positively regulates chondrocyte extracellular matrix metabolism. Cholesterol-induced down-regulation of LRP3 promotes cartilage degeneration by up-regulating syndecan-4 via activating the Ras signaling pathway [1]. Also, LRP3 knockdown suppresses chondrogenesis of stem cells, inhibits their proliferation, and promotes apoptosis [3]. In Alzheimer's disease-related pathology, the levels of LRP3 mRNA and protein are lower than in middle-aged individuals. Overexpression of ApoER2, a related protein, increases LRP3 expression. LRP3 transfection in cells reduces full-length APP levels and APP-CTF, and decreases levels of APP fragments from amyloidogenic and non-amyloidogenic pathways, as well as Aβ peptides [2].

In summary, LRP3 plays crucial roles in cartilage-related biological processes like chondrogenesis and extracellular matrix metabolism in osteoarthritis, and is also involved in APP processing potentially related to Alzheimer's disease. The use of Lrp3 KO mouse models and in vitro cell-based functional studies has been instrumental in uncovering these functions, providing insights into potential therapeutic strategies for these diseases.

References:

1. Cao, Chenxi, Shi, Yuanyuan, Zhang, Xin, Hu, Xiaoqing, Ao, Yingfang. 2022. Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4. In Nature communications, 13, 7139. doi:10.1038/s41467-022-34830-4. https://pubmed.ncbi.nlm.nih.gov/36414669/

2. Cuchillo-Ibañez, Inmaculada, Lennol, Matthew P, Escamilla, Sergio, Ferrer, Isidro, Sáez-Valero, Javier. 2021. The apolipoprotein receptor LRP3 compromises APP levels. In Alzheimer's research & therapy, 13, 181. doi:10.1186/s13195-021-00921-5. https://pubmed.ncbi.nlm.nih.gov/34727970/

3. Shi, Yuanyuan, Cao, Chenxi, Yang, Fan, Wang, Jianquan, Ao, Yingfang. 2022. Inhibition of LDL receptor-related protein 3 suppresses chondrogenesis of stem cells, inhibits proliferation, and promotes apoptosis. In Biochemical and biophysical research communications, 635, 77-83. doi:10.1016/j.bbrc.2022.10.035. https://pubmed.ncbi.nlm.nih.gov/36257195/

4. Ishii, H, Kim, D H, Fujita, T, Saeki, S, Yamamoto, T T. . cDNA cloning of a new low-density lipoprotein receptor-related protein and mapping of its gene (LRP3) to chromosome bands 19q12-q13. 2. In Genomics, 51, 132-5. doi:. https://pubmed.ncbi.nlm.nih.gov/9693042/