Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts

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  • Yeung, Ching-Yan Chloé
  • Richa Garva
  • Adam Pickard
  • Yinhui Lu
  • Venkatesh Mallikarjun
  • Joe Swift
  • Susan H. Taylor
  • Jyoti Rai
  • David R. Eyre
  • Mayank Chaturvedi
  • Yoshifumi Itoh
  • Qing Jun Meng
  • Cornelia Mauch
  • Paola Zigrino
  • Karl E. Kadler
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.
OriginalsprogEngelsk
TidsskriftMatrix Biology
Vol/bind124
Sider (fra-til)8-22
Antal sider15
ISSN0945-053X
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
The research was funded by Wellcome (110126/Z/15/Z and 203128/Z/16/Z) and the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/T001984/1) to KEK. CM and PZ were supported by Deutsche Forschungsgemeinschaft through SFB 829 (Project-ID 73111208-SFB829 (B4)). VM was supported by a studentship from the Sir Richard Stapley Educational Trust. JS was funded by a BBSRC David Phillips Fellowship (BB/L024551/1). MC and YI was funded by the Polish Ministry of Science & Higher Education (1291/MOB/IV/2015/0). Q-JM was supported by Medical Research Council project grants MR/T016744/1 and MR/P010709/1 and Versus Arthritis Senior Research Fellowship Award 20875. National Institutes of Health (NIH) Grant: (NIAMS) AR037318 to DRE. The authors would like to thank Ronen Schweitzer (Shriners Hospital for Children, Portland, OR, USA) for Scx-Cre mice, Jan Zamek, Alison Hallworth and Raymond Hodgkiss, and the University of Manchester Biological Support Facility for assistance in animal welfare and husbandry. Re-derivation of mouse strains and generation of expression vectors were performed by the Genome Editing Unit, University of Manchester. The proteomics was performed at the Biological Mass Spectrometry Facility in the Faculty of Biology, Medicine and Health (University of Manchester) with the assistance of Stacey Warwood and Ronan O'Cualain, and electron microscopy was performed in the Electron Microscopy Facility, Faculty of Biology, Medicine and Health (University of Manchester).

Funding Information:
The research was funded by Wellcome ( 110126/Z/15/Z and 203128/Z/16/Z ) and the Biotechnology and Biological Sciences Research Council (BBSRC) ( BB/T001984/1 ) to KEK. CM and PZ were supported by Deutsche Forschungsgemeinschaft through SFB 829 (Project- ID 73111208-SFB829 (B4) ). VM was supported by a studentship from the Sir Richard Stapley Educational Trust . JS was funded by a BBSRC David Phillips Fellowship ( BB/L024551/1 ). MC and YI was funded by the Polish Ministry of Science & Higher Education ( 1291/MOB/IV/2015/0 ). Q-JM was supported by Medical Research Council project grants MR/T016744/1 and MR/P010709/1 and Versus Arthritis Senior Research Fellowship Award 20875 . National Institutes of Health (NIH) Grant: (NIAMS) AR037318 to DRE. The authors would like to thank Ronen Schweitzer (Shriners Hospital for Children, Portland, OR, USA) for Scx-Cre mice, Jan Zamek, Alison Hallworth and Raymond Hodgkiss, and the University of Manchester Biological Support Facility for assistance in animal welfare and husbandry. Re-derivation of mouse strains and generation of expression vectors were performed by the Genome Editing Unit, University of Manchester. The proteomics was performed at the Biological Mass Spectrometry Facility in the Faculty of Biology, Medicine and Health (University of Manchester) with the assistance of Stacey Warwood and Ronan O'Cualain, and electron microscopy was performed in the Electron Microscopy Facility, Faculty of Biology, Medicine and Health (University of Manchester).

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© 2023 The Author(s)

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