Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

Abstract

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.

References 119

1. 1.

   Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell… and more. Endocr. Rev. 2013;34:658-690.

   Not in our library10.1210/er.2012-1026

2. 2.

   Kollmannsberger, P. et al. The small world of osteocytes: connectomics of the lacuno-canalicular network in bone. New J. Phys. 19, 073019 (2017).

   Not in our library

3. 3.

   Buenzli PR, Sims NA. Quantifying the osteocyte network in the human skeleton. Bone. 2015;75:144-150.

   Not in our library10.1016/j.bone.2015.02.016

4. 4.

   Schaffler MB, Cheung WY, Majeska R, Kennedy O. Osteocytes: master orchestrators of bone. Calcif. Tissue Int. 2014;94:5-24.

   Not in our library10.1007/s00223-013-9790-y

5. 5.

   Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu. Rev. Med. 2010;61:91-104.

   Not in our library10.1146/annurev.med.051308.111339

6. 6.

   Sato M, et al. Osteocytes regulate primary lymphoid organs and fat metabolism. Cell Metab. 2013;18:749-758.

   Not in our library10.1016/j.cmet.2013.09.014

7. 7.

   Asada N, et al. Matrix-embedded osteocytes regulate mobilization of hematopoietic stem/progenitor cells. Cell Stem Cell. 2013;12:737-747.

   Not in our library10.1016/j.stem.2013.05.001

8. 8.

   Shen H, Grimston S, Civitelli R, Thomopoulos S. Deletion of connexin43 in osteoblasts / osteocytes leads to impaired muscle formation in mice. J. Bone Miner. Res. 2015;30:596-605.

   Not in our library10.1002/jbmr.2389

9. 9.

   Forrest ARRR, et al. A promoter-level mammalian expression atlas. Nature. 2014;507:462-470.

   Not in our library10.1038/nature13182

10. 10.

    Lonsdale J, et al. The genotype-tissue expression (GTEx) project. Nat. Genet. 2013;45:580-585.

    Not in our library10.1038/ng.2653

11. 11.
    Expression Atlas update—an integrated database of gene and protein expression in humans, animals and plants · 2015

    No notice
12. 12.

    The Tabula Muris Consortium et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature. 2018.

    Not in our library10.1038/s41586-018-0590-4

13. 13.

    Ayturk UM, et al. An RNA-seq protocol to identify mRNA expression changes in mouse diaphyseal bone: applications in mice with bone property altering Lrp5 mutations. J. Bone Miner. Res. 2013;28:2081-2093.

    Not in our library10.1002/jbmr.1946

14. 14.

    Kelly NH, Schimenti JC, Ross FP, van der Meulen MCH. Transcriptional profiling of cortical versus cancellous bone from mechanically-loaded murine tibiae reveals differential gene expression. Bone. 2016;86:22-29.

    Not in our library10.1016/j.bone.2016.02.007

15. 15.

    Qing H, et al. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J. Bone Miner. Res. 2012;27:1018-1029.

    Not in our library10.1002/jbmr.1567

16. 16.

    Nioi P, et al. Transcriptional profiling of laser capture microdissected subpopulations of the osteoblast lineage provides insight into the early response to sclerostin antibody in rats. J. Bone Miner. Res. 2015;30:1457-1467.

    Not in our library10.1002/jbmr.2482

17. 17.

    Brunkow ME, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am. J. Hum. Genet. 2001;68:577-589.

    Not in our library10.1086/318811

18. 18.

    Balemans W, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 2001;10:537-543.

    Not in our library10.1093/hmg/10.5.537

19. 19.

    Balemans W, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J. Med. Genet. 2002;39:91-97.

    Not in our library10.1136/jmg.39.2.91

20. 20.

    Feng JQ, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet. 2006;38:1310-1315.

    Not in our library10.1038/ng1905

21. 21.

    Mortier GR, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am. J. Med. Genet. A. 2019.

    Not in our library10.1002/ajmg.a.61366

22. 22.

    Videman T, et al. Heritability of BMD of femoral neck and lumbar spine: a multivariate twin study of Finnish men. J. Bone Miner. Res. 2007;22:1455-1462.

    Not in our library10.1359/jbmr.070606

23. 23.

    Karasik D, et al. Mapping of quantitative ultrasound of the calcaneus bone to chromosome 1 by genome-wide linkage analysis. Osteoporos. Int. 2002;13:796-802.

    Not in our library10.1007/s001980200110

24. 24.

    Valdes AM, Spector TD. Genetic epidemiology of hip and knee osteoarthritis. Nat. Rev. Rheumatol. 2011;7:23-32.

    Not in our library10.1038/nrrheum.2010.191

25. 25.

    Morris JA, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat. Genet. 2019;51:258-266.

    Not in our library10.1038/s41588-018-0302-x

26. 26.

    Zengini E, et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat. Genet. 2018;50:549-558.

    Not in our library10.1038/s41588-018-0079-y

27. 27.
    Finding the active genes in deep RNA-seq gene expression studies · 2013

    No notice
28. 28.

    Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: Implications for biology and medicine. Proc. Natl Acad. Sci. USA. 2014;111:16219-16224.

    Not in our library10.1073/pnas.1408886111

29. 29.

    Yanai I, et al. Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification. Bioinformatics. 2005;21:650-659.

    Not in our library10.1093/bioinformatics/bti042

30. 30.

    Agarwal P, et al. Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo. Development. 2003;130:623-633.

    Not in our library10.1242/dev.00191

31. 31.

    Takeuchi JK, et al. Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature. 1999;398:810-814.

    Not in our library10.1038/19762

32. 32.

    DeLaurier A, Schweitzer R, Logan M. Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb. Dev. Biol. 2006;299:22-34.

    Not in our library10.1016/j.ydbio.2006.06.055

33. 33.

    Spielmann M, et al. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am. J. Hum. Genet. 2012;91:629-635.

    Not in our library10.1016/j.ajhg.2012.08.014

34. 34.

    Richman C, et al. Postnatal and pubertal skeletal changes contribute predominantly to the differences in peak bone density between C3H/HeJ and C57BL/6J mice. J. Bone Miner. Res. 2001;16:386-397.

    Not in our library10.1359/jbmr.2001.16.2.386

35. 35.

    Cole TJ, et al. Ethnic and sex differences in skeletal maturation among the Birth to Twenty cohort in South Africa. Arch. Dis. Child. 2015;100:138-143.

    Not in our library10.1136/archdischild-2014-306399

36. 36.

    Baxter-Jones ADG, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: An estimation of peak bone mass. J. Bone Miner. Res. 2011;26:1729-1739.

    Not in our library10.1002/jbmr.412

37. 37.

    Jähn K, et al. Osteocytes acidify their microenvironment in response to PTHrP in vitro and in lactating mice in vivo. J. Bone Miner. Res. 2017;32:1761-1772.

    Not in our library10.1002/jbmr.3167

38. 38.

    Plotkin LI, Bellido T. Osteocytic signalling pathways as therapeutic targets for bone fragility. Nat. Rev. Endocrinol. 2016;12:593-605.

    Not in our library10.1038/nrendo.2016.71

39. 39.

    Taylor S, et al. Differential time-dependent transcriptional changes in the osteoblast lineage in cortical bone associated with sclerostin antibody treatment in ovariectomized rats. Bone Rep. 2018;8:95-103.

    Not in our library10.1016/j.bonr.2018.03.002

40. 40.

    Ashburner M, et al. Gene ontology: tool for the unification of biology. Nat. Genet. 2000;25:25-29.

    Not in our library10.1038/75556

Cited by papers we hold 3

• Osteoclast-independent osteocyte dendrite defects in mice bearing the osteogenesis imperfecta-causing Sp7 R342C mutation · 2025
  Not checked
• Systemic immune-inflammation index and bone mineral density in postmenopausal women: A cross-sectional study of the national health and nutrition examination survey (NHANES) 2007-2018 · 2022
  No notice
• Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption · 2021
  Corrected

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.