{"doi":"10.1101/2022.03.02.482546","title":"Uncovering the ligandome of low-density lipoprotein receptor-related protein 1 in cartilage: a top-down approach to identify therapeutic targets","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  The low-density lipoprotein receptor-related protein 1 (LRP1) is a cell-surface receptor ubiquitously expressed in adult tissues. It plays tissue-specific physiological roles by mediating endocytosis of a diverse range of extracellular molecules. Dysregulation of LRP1 is involved in multiple conditions including Alzheimer’s disease, atherosclerosis and osteoarthritis (OA). However, little information is available about the specific ligand profile (ligandome) for each tissue, which would lead to better understanding of its role in disease states. Here, we investigated adult articular cartilage where impaired LRP1-mediated endocytosis leads to tissue destruction. We used a top-down approach involving analysis of human chondrocyte secretome, direct binding assays and validation in LRP1-deficient fibroblasts, as well as a novel\n                  <jats:italic>Lrp1</jats:italic>\n                  conditional knockout (KO) mouse model. We found that inhibition of LRP1-mediated endocytosis results in cell death, alteration of the entire secretome and transcriptional modulations in human chondrocytes. We have identified more than 50 novel ligand candidates and confirmed direct LRP1 binding of\n                  <jats:italic>HGFAC</jats:italic>\n                  ,\n                  <jats:italic>HMGB1</jats:italic>\n                  ,\n                  <jats:italic>HMGB2</jats:italic>\n                  ,\n                  <jats:italic>CEMIP</jats:italic>\n                  ,\n                  <jats:italic>SLIT2</jats:italic>\n                  ,\n                  <jats:italic>ADAMTS1</jats:italic>\n                  ,\n                  <jats:italic>IGFBP7</jats:italic>\n                  ,\n                  <jats:italic>SPARC</jats:italic>\n                  and\n                  <jats:italic>LIF</jats:italic>\n                  . Our\n                  <jats:italic>in vitro</jats:italic>\n                  endocytosis assay revealed the correlation of their affinity for LRP1 and the rate of endocytosis. Moreover, a conditional LRP1 KO mouse model demonstrated a critical role of LRP1 in regulating the high-affinity ligands in cartilage\n                  <jats:italic>in vivo</jats:italic>\n                  . This systematic approach revealed the extent of the chondrocyte LRP1 ligandome and identified potential novel therapeutic targets for OA.\n                </jats:p>","journal":null,"year":null,"id":639869,"datarank":0.1807154947455125,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.01592365144529604,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.01592365144529604,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":298028,"name":"Carsten Scavenius","orcid":"0000-0002-4304-0681","position":1,"is_corresponding":false},{"id":1662808,"name":"Maria M Meschis","orcid":null,"position":2,"is_corresponding":false},{"id":1662809,"name":"Emilie H Mogensen","orcid":null,"position":3,"is_corresponding":false},{"id":1662810,"name":"Abdulrahman M E Gremida","orcid":null,"position":4,"is_corresponding":false},{"id":1662811,"name":"Ida B Thøgersen","orcid":null,"position":5,"is_corresponding":false},{"id":421905,"name":"Simone Bonelli","orcid":"0009-0003-7789-2502","position":6,"is_corresponding":false},{"id":421911,"name":"Simone Dario Scilabra","orcid":"0000-0001-7300-6153","position":7,"is_corresponding":false},{"id":665085,"name":"Salvatore Santamaria","orcid":"0000-0001-8670-7776","position":8,"is_corresponding":false},{"id":665086,"name":"Josefin Ahnström","orcid":"0000-0001-5313-6508","position":9,"is_corresponding":false},{"id":500665,"name":"George Bou–Gharios","orcid":"0000-0002-9563-9418","position":10,"is_corresponding":false},{"id":298029,"name":"Jan J. Enghild","orcid":"0000-0001-9292-9172","position":11,"is_corresponding":false},{"id":421910,"name":"Hideaki Nagase","orcid":"0000-0002-8563-2263","position":12,"is_corresponding":false},{"id":699009,"name":"Kazuhiro Yamamoto","orcid":"0000-0002-8481-775X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Uncovering the ligandome of low-density lipoprotein receptor-related protein 1 in cartilage: a top-down approach to identify therapeutic targets","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  The low-density lipoprotein receptor-related protein 1 (LRP1) is a cell-surface receptor ubiquitously expressed in adult tissues. It plays tissue-specific physiological roles by mediating endocytosis of a diverse range of extracellular molecules. Dysregulation of LRP1 is involved in multiple conditions including Alzheimer’s disease, atherosclerosis and osteoarthritis (OA). However, little information is available about the specific ligand profile (ligandome) for each tissue, which would lead to better understanding of its role in disease states. Here, we investigated adult articular cartilage where impaired LRP1-mediated endocytosis leads to tissue destruction. We used a top-down approach involving analysis of human chondrocyte secretome, direct binding assays and validation in LRP1-deficient fibroblasts, as well as a novel\n                  <jats:italic>Lrp1</jats:italic>\n                  conditional knockout (KO) mouse model. We found that inhibition of LRP1-mediated endocytosis results in cell death, alteration of the entire secretome and transcriptional modulations in human chondrocytes. We have identified more than 50 novel ligand candidates and confirmed direct LRP1 binding of\n                  <jats:italic>HGFAC</jats:italic>\n                  ,\n                  <jats:italic>HMGB1</jats:italic>\n                  ,\n                  <jats:italic>HMGB2</jats:italic>\n                  ,\n                  <jats:italic>CEMIP</jats:italic>\n                  ,\n                  <jats:italic>SLIT2</jats:italic>\n                  ,\n                  <jats:italic>ADAMTS1</jats:italic>\n                  ,\n                  <jats:italic>IGFBP7</jats:italic>\n                  ,\n                  <jats:italic>SPARC</jats:italic>\n                  and\n                  <jats:italic>LIF</jats:italic>\n                  . Our\n                  <jats:italic>in vitro</jats:italic>\n                  endocytosis assay revealed the correlation of their affinity for LRP1 and the rate of endocytosis. Moreover, a conditional LRP1 KO mouse model demonstrated a critical role of LRP1 in regulating the high-affinity ligands in cartilage\n                  <jats:italic>in vivo</jats:italic>\n                  . This systematic approach revealed the extent of the chondrocyte LRP1 ligandome and identified potential novel therapeutic targets for OA.\n                </jats:p>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19767382","pmcid":null,"openalex_id":"https://openalex.org/W4214939823","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2023,"count":2}],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1101/2022.03.02.482546","host_type":"repository"},{"url":"https://doi.org/10.1101/2022.03.02.482546","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2022.03.02.482546","host_type":"publisher"},{"url":"http://hdl.handle.net/10044/1/103110","host_type":"repository"}],"fields_of_study":["Protease and Inhibitor Mechanisms","Calpain Protease Function and Regulation","Cell Adhesion Molecules Research"],"mesh_terms":[],"keywords":["LRP1","Endocytosis","LDL receptor","Cell biology","Chondrocyte","Conditional gene knockout","Receptor","Biology","Chemistry","Lipoprotein","In vitro","Biochemistry","Cholesterol","Phenotype","Gene"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-07T03:27:22.908587Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}