{"doi":"10.1101/2025.11.24.690319","title":"Sensorineural regulation of skull healing implicates FGF1 signaling in non-healing bone","abstract":"Bone injuries demonstrate rapid peripheral nerve ingrowth followed by nerve pruning as healing ensues. However, in non-healing bone injuries, peripheral innervation remains elevated, the implications of which remain unknown. Therefore, we investigated the neuroskeletal microenvironment in subcritical-and critical-sized calvarial defects using quantitative 3D fluorescence imaging. We identified elevated densities of peripheral nerves and Osterix positive (Osx+) osteoprogenitors in critical-sized defects, while osteogenic differentiation markers were severely diminished. Moreover, Osx+ osteoprogenitors in critical-sized defects exhibited enhanced proximity to peripheral nerves, which in turn was associated with increased osteoprogenitor cell proliferation. Using retrograde tracing in conjunction with single cell RNA-sequencing of sensory nerves from the innervating trigeminal ganglia, genes encoding for nerve-secreted proliferative and anti-differentiation factors were identified. Specifically, FGF-1/FGFR-1 signaling was identified as a significant neuroskeletal interaction with critical-sized defects demonstrating higher FGF-1 expression in fluorescence imaging. Presence of FGF-1 in neurons innervating the calvarial was confirmed, and neural conditioned media depleted for FGF1 showed enhanced induction of osteogenesis when placed on parietal bone cells. Collectively, we identify a sensorineural-skeletal signaling interaction elevated in critical-sized defects that can be leveraged as a potential therapeutic target for enhancing bone healing.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":583568,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"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":1067448,"name":"Carlos U. Villapudua","orcid":"0000-0002-5026-4384","position":1,"is_corresponding":false},{"id":951198,"name":"Mingxin Xu","orcid":"0009-0002-5228-3623","position":2,"is_corresponding":false},{"id":800689,"name":"Eric Z. Zeng","orcid":null,"position":3,"is_corresponding":false},{"id":938200,"name":"Shaquielle Dias","orcid":"0000-0002-2093-8026","position":4,"is_corresponding":false},{"id":1414940,"name":"Tanishk Sinha","orcid":null,"position":5,"is_corresponding":false},{"id":1096389,"name":"Mary Archer","orcid":null,"position":6,"is_corresponding":false},{"id":246988,"name":"Erica L. Scheller","orcid":"0000-0002-1551-3816","position":7,"is_corresponding":false},{"id":827614,"name":"Arvind P. Pathak","orcid":"0000-0002-2068-9445","position":8,"is_corresponding":false},{"id":250819,"name":"Aaron W. James","orcid":"0000-0002-2002-622X","position":9,"is_corresponding":false},{"id":362359,"name":"Warren L. Grayson","orcid":"0000-0001-6099-6469","position":10,"is_corresponding":false},{"id":765542,"name":"Allison L Horenberg","orcid":"0000-0002-4011-5430","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:59:07.970345Z","pmid":"41394567","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":[]}