Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
Bibliographical noteFunding Information:
This work was supported by a Wellcome Trust Strategic Award (101123/Z/13/A) to G.R. W, P.I.C. and J.H.D.B, and by Mrs Janice Gibson and the Ernest Heine Family Foundation. P.I.C is supported by Mrs Janice Gibson and the Ernest Heine Family Foundation. J.H.D.B and G.R.W received a Wellcome Trust Joint Investigator Award (110141/Z/ 15/Z and 110140/Z/15/Z) and EU H2020 THYRAGE Grant (666869). S.E.Y and A.P.C were funded by the Australian Government Research Training Program Scholarships. J. P.K was funded by a University of Queensland Development Fellowship (UQFEL1718945), a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938) and project grant (GNT1158758). J.T.S was funded by a University International Postgraduate Award Scholarship (UNSW). J.A.M was funded by a Banting Postdoctoral Fellowship. J.M.W.Q was funded by an Australian National Health and Medical Research Council project grant (ID: GNT1057706). M.J was funded by Viapath. J.B.R was supported by the Canadian Institutes of Health Research (CIHR), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK and the Fonds de Recherche Québec Santé (FRQS). J.B.R. is supported by a FRQS Clinical Research Scholarship. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. D.J.A and C.J.L were funded by Wellcome Trust Strategic Awards. D.M.E. was funded by an Australian National Health and Medical Research Council Senior Research Fellowship (APP1137714). T.G.P was funded by an Australian National Health and Medical Research Council Senior Research Fellowship (1155678). This research has been conducted using the UK Biobank Resource (accession IDs: 12703). This work was assisted by phenotyping expertise provided by Anne-Tounsia Adoum, Justyna Miszkiewicz, Rebecca Allen, Jayashree Bagchi Chakraborty, Katharine F Curry, Hannah F. Dewhurst, Apos-tolos Gogakos, Naila Mannan, Hayley J Protheroe, Penny C Sparkes, Valerie Vancollie and Fiona Kussy. Ya Xiao assisted with animal studies. The Sanger Institute’s Research Support Facility, Mouse Pipelines and Mouse Informatics Group generated mice and collected materials for this manuscript. This research has been conducted using the UK Biobank Resource (accession ID: 53641).
© 2021, The Author(s).