Osteocytes express a unique transcriptome that underpins skeletal homeostasis — ASN Events
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Osteocytes express a unique transcriptome that underpins skeletal homeostasis (#59)

Scott E Youlten 1 2 , Paul A Baldock 1 2 , Victoria D Leitch 3 , Julian M W Quinn 1 , Nenad Bartonicek 4 , Ryan C Chai 1 , John A Eisman 1 5 , J. H. Duncan Bassett 3 , Graham R Williams 3 , Peter I Croucher 1 2
  1. The Division of Bone Biology, The Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia
  3. Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, W12 0NN, United Kingdom
  4. Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia
  5. School of Medicine Sydney, University of Notre Dame Australia, Sydney, NSW, Australia

Osteocytes are pivotal regulators of skeletal homeostasis, communicating between the bone-cell lineages to coordinate activity. However, little is known of the pattern of coding and non-coding genes expressed by these cells, as the skeleton is frequently omitted from large-scale efforts to map tissue-specific transcriptomes. We hypothesised that osteocytes express a unique transcriptome, defining key signalling-pathways used to orchestrate bone turnover and skeletal homeostasis. Transcriptome-sequencing was performed on total-RNA extracted from osteocytes isolated from the tibiae, femora, humeri and calvariae of 16-week-old CB57BL6/NTac mice (n=8). De novo transcriptome-assembly was performed and gene-expression quantified. Osteocytes expressed a repertoire of ~12000 genes common across all bone types, 1197 of which were more than 4-fold enriched in osteocytes relative to bone marrow, thereby defining an osteocyte transcriptome signature. Osteocytes derived from different anatomical locations could be distinguished by unique patterns of homeobox-gene expression, including Hoxc and Hoxd clusters, and Pitx1. Of the ~880 lncRNAs expressed within osteocytes, 52 were present in the signature, including novel lncRNAs with osteocyte-restricted expression. In addition to highly enriched osteocyte genes such as Sost, Mepe and Dmp1, more than 80% of signature genes had not previously been annotated with a skeletal function in the Gene Ontology database. The osteocyte signature was highly enriched for pathways regulating axonal guidance, suggesting that osteocytes have repurposed neuronal pathways to control networking functions and facilitate intercellular communication between osteocytes and bone-cell lineages. Genes known to cause skeletal dysplasia were significantly enriched in the osteocyte signature (p=4.9E-16), including more than 80% of genes known to cause Osteogenesis Imperfecta, suggesting the signature may prove valuable in identifying causal variants for unexplained skeletal conditions by acting as a filter for patient genomic data. This study has defined the osteocyte transcriptome and provided important insights into the molecular pathways that control osteocyte biology and skeletal disorders.