A top-down approach to uncover the hidden ligandome of low-density lipoprotein receptor-related protein 1 in cartilage

•Inhibition of LRP1 and ligand interaction results in cell death, alteration of the entire secretome and transcriptional modulations in human chondrocytes.•Chondrocyte specific profile of direct binding partners of LRP1 (ligandome) consists of more than 50 novel ligand candidates.•LRP1 directly binds to HGFAC, HMGB1, HMGB2, CEMIP, SLIT2, ADAMTS1, TSG6, IGFBP7, SPARC and LIF.•LRP1 KO Novel conditional mouse model demonstrated a critical role of LRP1 in regulating the high-affinity ligands in cartilage in vivo.•The methodology established in this study could be useful for other tissue contexts and diseases.