Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts. / Yeung, Ching Yan Chloé; Garva, Richa; Pickard, Adam; Lu, Yinhui; Mallikarjun, Venkatesh; Swift, Joe; Taylor, Susan H.; Rai, Jyoti; Eyre, David R.; Chaturvedi, Mayank; Itoh, Yoshifumi; Meng, Qing Jun; Mauch, Cornelia; Zigrino, Paola; Kadler, Karl E.
In: Matrix Biology, Vol. 124, 2023, p. 8-22.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts
AU - Yeung, Ching Yan Chloé
AU - Garva, Richa
AU - Pickard, Adam
AU - Lu, Yinhui
AU - Mallikarjun, Venkatesh
AU - Swift, Joe
AU - Taylor, Susan H.
AU - Rai, Jyoti
AU - Eyre, David R.
AU - Chaturvedi, Mayank
AU - Itoh, Yoshifumi
AU - Meng, Qing Jun
AU - Mauch, Cornelia
AU - Zigrino, Paola
AU - Kadler, Karl E.
N1 - Publisher Copyright: © 2023 The Author(s)
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Cell surface enzyme
KW - Circadian rhythm
KW - Collagen
KW - Connective tissue
KW - CRISPR/Cas-9
KW - Electron microscopy
KW - Gene knockout
KW - Matrix metalloproteinase (MMP)
KW - Protein self-assembly
KW - Tendon
U2 - 10.1016/j.matbio.2023.10.002
DO - 10.1016/j.matbio.2023.10.002
M3 - Journal article
C2 - 37913834
AN - SCOPUS:85177087950
VL - 124
SP - 8
EP - 22
JO - Matrix Biology
JF - Matrix Biology
SN - 0945-053X
ER -
ID: 374665447