title: Gremlin-2 is a BMP antagonist that is regulated by the circadian clock.
abstract: 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 CLOCKΔ19 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.
authors.affiliation: 1] Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom [2] Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Ching-Yan Chloé
authors.initials: CY
authors.lastname: Yeung
authors.affiliation: 1] Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom [2] Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Nicole
authors.initials: N
authors.lastname: Gossan
authors.affiliation: 1] Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom [2] Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Yinhui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Alun
authors.initials: A
authors.lastname: Hughes
authors.affiliation: Department of Computer Science, University of Sheffield, Sheffield S1 4DP, United Kingdom.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hensman
authors.affiliation: Institute of Sports Medicine, Department of Orthopedic Surgery M, Bispebjerg Hospital, and Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, 2400 Copenhagen, Denmark.
authors.forename: Monika L
authors.initials: ML
authors.lastname: Bayer
authors.affiliation: Institute of Sports Medicine, Department of Orthopedic Surgery M, Bispebjerg Hospital, and Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, 2400 Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Kjær
authors.affiliation: 1] Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom [2] Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Kadler
authors.affiliation: 1] Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom [2] Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D057906:Circadian Clocks / Q000502:physiology*; D016207:Cytokines; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013710:Tendons / Q000166:cytology / Q000502:physiology*; D013997:Time Factors
chemical_list: C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D016207:Cytokines; C490088:Grem2 protein, mouse; D011506:Proteins; D012333:RNA, Messenger