title: Transcriptional profiling of cortical versus cancellous bone from mechanically-loaded murine tibiae reveals differential gene expression.
abstract: Mechanical loading is an anabolic stimulus that increases bone mass, and thus a promising method to counteract osteoporosis-related bone loss. The mechanism of this anabolism remains unclear, and needs to be established for both cortical and cancellous envelopes individually. We hypothesized that cortical and cancellous bone display different gene expression profiles at baseline and in response to mechanical loading. To test this hypothesis, the left tibiae of 10-week-old female C57Bl/6 mice were subjected to one session of axial tibial compression (9N, 1200cycles, 4Hz triangle waveform) and euthanized 3 and 24h following loading. The right limb served as the contralateral control. We performed RNA-seq on marrow-free metaphyseal samples from the cortical shell and the cancellous core to determine differential gene expression at baseline (control limb) and in response to load. Differential expression was verified with qPCR. Cortical and cancellous bone exhibited distinctly different transcriptional profiles basally and in response to mechanical loading. More genes were differentially expressed with loading at 24h with more genes downregulated at 24h than at 3h in both tissues. Enhanced Wnt signaling dominated the response in cortical bone at 3 and 24h, but in cancellous bone only at 3h. In cancellous bone at 24h many muscle-related genes were downregulated. These findings reveal key differences between cortical and cancellous genetic regulation in response to mechanical loading. Future studies at different time points and multiple loading sessions will add to our knowledge of cortical and cancellous mechanotransduction with the potential to identify new targets for mouse genetic knockout studies and drugs to treat osteoporosis.
authors.affiliation: Sibley School of Mechanical and Aerospace Engineering, Cornell University, 105 Upson Hall, Ithaca, NY 14853, USA; Nancy E and Peter C Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, Ithaca, NY 14853, USA. Electronic address: nhk28@cornell.edu.
authors.forename: Natalie H
authors.initials: NH
authors.lastname: Kelly
authors.affiliation: College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. Electronic address: jcs92@cornell.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Schimenti
authors.affiliation: Research Division, Hospital for Special Surgery, 541 East 71st St., New York, NY 10021, USA. Electronic address: RossF@hss.edu.
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.affiliation: Sibley School of Mechanical and Aerospace Engineering, Cornell University, 105 Upson Hall, Ithaca, NY 14853, USA; Nancy E and Peter C Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, Ithaca, NY 14853, USA; Research Division, Hospital for Special Surgery, 541 East 71st St., New York, NY 10021, USA. Electronic address: mcv3@cornell.edu.
authors.forename: Marjolein C H
authors.initials: MC
authors.lastname: van der Meulen
mesh_terms: D000818:Animals; D000071556:Cancellous Bone / Q000378:metabolism*; D000071538:Cortical Bone / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D013314:Stress, Mechanical; D013977:Tibia / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D014158:Transcription, Genetic; D016474:Weight-Bearing; D060449:Wnt Signaling Pathway / Q000235:genetics
keywords: Animal models; Cancellous bone; Cortical bone; Mechanical loading; Osteoporosis; Transcriptome