Low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6)

Low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) are highly homologous single-pass transmembrane receptors that serve as essential co-receptors for the canonical Wnt/beta-catenin signaling pathway [1, 2]. They function by forming a ternary complex with Wnt ligands and Frizzled receptors, which triggers a cascade leading to the stabilization of beta-catenin and its translocation to the nucleus to activate gene transcription [4, 7]. These receptors play a fundamental role in regulating bone mineral density, retinal vascularization, and lipid metabolism, and are vital for embryonic development and adult tissue homeostasis [10, 12]. Mutations in LRP5/6 are linked to diverse pathologies, including osteoporosis-pseudoglioma syndrome, high bone mass disorders, and familial exudative vitreoretinopathy [2, 10]. In oncology, LRP5/6 are frequently overexpressed or hyperactivated, contributing to the progression of colorectal, breast, and pancreatic cancers [6, 11]. Therapeutic strategies include the use of antagonists to inhibit tumor growth and agonists or indirect modulators (such as sclerostin inhibitors) to promote bone formation and tissue repair [15, 19, 21].

Other names

LRP5LRP6Low-density lipoprotein receptor-related protein 5Low-density lipoprotein receptor-related protein 6BMND1EVR1OPPGHBMADCAD2Wnt co-receptor LRP5/6

Drugs targeting LRP5/6 primarily act by either antagonizing or agonizing the canonical Wnt/beta-catenin signaling pathway. Antagonists, such as monoclonal antibodies or nanobodies, bind to the extracellular domains of LRP5/6 to block Wnt ligand interaction, thereby inhibiting aberrant signaling in cancers like colorectal or breast cancer [18, 19]. Agonists, including bispecific antibodies, promote the heterodimerization of LRP5/6 with Frizzled receptors to activate signaling for tissue regeneration in bone, eye, or intestinal diseases [23, 27]. Additionally, indirect modulators like Romosozumab block natural inhibitors (e.g., Sclerostin or DKK1) from binding to LRP5/6, thereby enhancing Wnt-mediated bone formation [15, 16].