{"doi":"10.3389/fendo.2024.1523931","title":"Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivity","abstract":"Recombinant human IGF-1 is used to treat severe primary IGF-1 deficiency, but this treatment requires twice-daily injection, often does not fully correct the growth deficit, and has important off-target effects. We therefore sought to target IGF-1 to growth plate cartilage by generating fusion proteins combining IGF-1 with single-chain human antibody fragments that target matrilin-3, a cartilage matrix protein. We previously showed that this cartilage-targeting IGF-1 fusion protein (CV1574-1) promoted growth plate function in a GH-deficient (lit) mouse model. Here, we studied CV1574-1 in a second mouse model, C57BL/6 wild-type mice treated with pegvisomant to induce GH resistance. In this model, once-daily injections of CV1574-1 for 5 days partially restored the pegvisomant-induced decrease in growth plate height without increasing kidney cell proliferation. Furthermore, we found that subcutaneous CV1574-1 showed significantly reduced hypoglycemic effect compared to injection of IGF-1 itself. Lastly, to gain mechanistic insights into the role of matrilin-3 targeting, we assessed the ability of CV1574-1 to activate AKT signaling in vitro and found that CV1574-1 caused a prolonged increase in AKT signaling compared to IGF-1 and that this effect was dependent on matrilin-3. Taken together, our findings provide further evidence that cartilage-targeted therapy could provide new pharmacological approaches for the treatment of childhood growth disorders, such as GH-insensitivity syndrome.","journal":"Frontiers in Endocrinology","year":2025,"id":540031,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1427908,"name":"Janine H. van Ree","orcid":null,"position":1,"is_corresponding":false},{"id":1427909,"name":"Timothy R. Stowe","orcid":null,"position":2,"is_corresponding":false},{"id":1427910,"name":"Brit Ventura","orcid":null,"position":3,"is_corresponding":false},{"id":1427911,"name":"Connor Sisk","orcid":null,"position":4,"is_corresponding":false},{"id":1427912,"name":"Joanna Courtis","orcid":null,"position":5,"is_corresponding":false},{"id":1427913,"name":"Anna Camp","orcid":null,"position":6,"is_corresponding":false},{"id":1135373,"name":"Fatima D. Elzamzami","orcid":null,"position":7,"is_corresponding":false},{"id":280202,"name":"Jan van Deursen","orcid":null,"position":8,"is_corresponding":false},{"id":1427481,"name":"Robert O’Brien","orcid":"0000-0002-8203-6239","position":9,"is_corresponding":false},{"id":1116294,"name":"Jeffrey Baron","orcid":"0000-0002-9985-3403","position":10,"is_corresponding":false},{"id":21707,"name":"Julian C. Lui","orcid":"0000-0002-0611-4901","position":11,"is_corresponding":false},{"id":311316,"name":"Krishma Tailor","orcid":"0000-0001-6507-7218","position":0,"is_corresponding":true}],"reference_count":24,"raw_metadata":null,"created_at":"2026-07-19T02:52:34.520788Z","pmid":"39850478","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":[]}