Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Gremlin-2 is a BMP antagonist that is regulated by the circadian clock
AU - Yeung, Ching Yan Chloé
AU - Gossan, Nicole
AU - Lu, Yinhui
AU - Hughes, Alun
AU - Hensman, James J.
AU - Bayer, Monika L.
AU - Kjær, Michael
AU - Kadler, Karl E.
AU - Meng, Qing Jun
PY - 2014/6/5
Y1 - 2014/6/5
N2 - Tendons are prominent members of the family of fibrous connective tissues (FCTs), which collectively are the most abundant tissues in vertebrates and have crucial roles in transmitting mechanical force and linking organs. Tendon diseases are among the most common arthropathy disorders; thus knowledge of tendon gene regulation is essential for a complete understanding of FCT biology. Here we show autonomous circadian rhythms in mouse tendon and primary human tenocytes, controlled by an intrinsic molecular circadian clock. Time-series microarrays identified the first circadian transcriptome of murine tendon, revealing that 4.6% of the transcripts (745 genes) are expressed in a circadian manner. One of these genes was Grem2, which oscillated in antiphase to BMP signaling. Moreover, recombinant human Gremlin-2 blocked BMP2-induced phosphorylation of Smad1/5 and osteogenic differentiation of human tenocytes in vitro. We observed dampened Grem2 expression, deregulated BMP signaling, and spontaneously calcifying tendons in young CLOCKÎ "19 arrhythmic mice and aged wild-type mice. Thus, disruption of circadian control, through mutations or aging, of Grem2/BMP signaling becomes a new focus for the study of calcific tendinopathy, which affects 1-in-5 people over the age of 50 years.
AB - Tendons are prominent members of the family of fibrous connective tissues (FCTs), which collectively are the most abundant tissues in vertebrates and have crucial roles in transmitting mechanical force and linking organs. Tendon diseases are among the most common arthropathy disorders; thus knowledge of tendon gene regulation is essential for a complete understanding of FCT biology. Here we show autonomous circadian rhythms in mouse tendon and primary human tenocytes, controlled by an intrinsic molecular circadian clock. Time-series microarrays identified the first circadian transcriptome of murine tendon, revealing that 4.6% of the transcripts (745 genes) are expressed in a circadian manner. One of these genes was Grem2, which oscillated in antiphase to BMP signaling. Moreover, recombinant human Gremlin-2 blocked BMP2-induced phosphorylation of Smad1/5 and osteogenic differentiation of human tenocytes in vitro. We observed dampened Grem2 expression, deregulated BMP signaling, and spontaneously calcifying tendons in young CLOCKÎ "19 arrhythmic mice and aged wild-type mice. Thus, disruption of circadian control, through mutations or aging, of Grem2/BMP signaling becomes a new focus for the study of calcific tendinopathy, which affects 1-in-5 people over the age of 50 years.
U2 - 10.1038/srep05183
DO - 10.1038/srep05183
M3 - Journal article
AN - SCOPUS:84902106530
VL - 4
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 5183
ER -