{"doi":"10.1101/2022.04.01.486699","title":"Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts","abstract":"ABSTRACT The circadian clock in tendon regulates the daily rhythmic synthesis of collagen-I and the appearance and disappearance of small-diameter collagen fibrils in the extracellular matrix. How the fibrils are assembled and removed is not fully understood. Here, we first showed that the collagenase, membrane type I-matrix metalloproteinase (MT1-MMP, encoded by Mmp14 ), is regulated by the circadian clock in postnatal mouse tendon. Next, we generated tamoxifen-induced Col1a2-Cre-ERT2::Mmp14 KO mice ( Mmp14 conditional knockout (CKO)). The CKO mice developed hind limb dorsiflexion and thickened tendons, which accumulated narrow-diameter collagen fibrils causing ultrastructural disorganization. Mass spectrometry of control tendons identified 1195 proteins of which 212 showed time-dependent abundance. In Mmp14 CKO mice 19 proteins had reversed temporal abundance and 176 proteins lost time dependency. Among these, the collagen crosslinking enzymes lysyl oxidase-like 1 (LOXL1) and lysyl hydroxylase 1 (LH1; encoded by Plod2 ) were elevated and had lost time-dependent regulation. High-pressure chromatography confirmed elevated levels of hydroxylysine aldehyde (pyridinoline) crosslinking of collagen in CKO tendons. As a result, collagen-I was refractory to extraction. We also showed that CRISPR-Cas9 deletion of Mmp14 from cultured fibroblasts resulted in loss of circadian clock rhythmicity of period 2 (PER2), and recombinant MT1-MMP was highly effective at cleaving soluble collagen-I but less effective at cleaving collagen pre-assembled into fibrils. In conclusion, our study shows that circadian clock-regulated Mmp14 controls the rhythmic synthesis of small diameter collagen fibrils, regulates collagen crosslinking, and its absence disrupts the circadian clock and matrisome in tendon fibroblasts.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":303055,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":995100,"name":"Richa Garva","orcid":"0000-0001-7752-8936","position":1,"is_corresponding":false},{"id":995101,"name":"Adam Pickard","orcid":"0000-0001-9757-143X","position":2,"is_corresponding":false},{"id":405430,"name":"Yinhui Lu","orcid":"0000-0001-9034-0823","position":3,"is_corresponding":false},{"id":995102,"name":"Venkatesh Mallikarjun","orcid":"0000-0002-0284-5205","position":4,"is_corresponding":false},{"id":995103,"name":"Joe Swift","orcid":"0000-0002-5039-9094","position":5,"is_corresponding":false},{"id":995104,"name":"Susan H. Taylor","orcid":"0000-0001-9554-055X","position":6,"is_corresponding":false},{"id":492546,"name":"Jyoti Rai","orcid":"0000-0001-6101-739X","position":7,"is_corresponding":false},{"id":365011,"name":"David R. Eyre","orcid":"0000-0003-2605-8545","position":8,"is_corresponding":false},{"id":995105,"name":"Mayank Chaturvedi","orcid":"0000-0002-9380-1805","position":9,"is_corresponding":false},{"id":995106,"name":"Yoshifumi Itoh","orcid":"0000-0002-2128-2823","position":10,"is_corresponding":false},{"id":815080,"name":"Qing‐Jun Meng","orcid":"0000-0002-9426-8336","position":11,"is_corresponding":false},{"id":995107,"name":"Cornelia Mauch","orcid":"0000-0002-3989-0536","position":12,"is_corresponding":false},{"id":995108,"name":"Paola Zigrino","orcid":"0000-0002-7470-0064","position":13,"is_corresponding":false},{"id":405431,"name":"Karl E. Kadler","orcid":"0000-0003-4977-4683","position":14,"is_corresponding":false},{"id":995099,"name":"Ching‐Yan Chloé Yeung","orcid":"0000-0002-7076-8109","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-19T00:32:20.348385Z","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":[]}