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Cited by 1Bone and Dental Protein StudiesBone health and osteoporosis researchBone Metabolism and Diseases

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Bone mechano-response is driven by locomotion transitions during vertebrate evolution

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Shimochi, Saeka, Brunet, Clara, Fontcuberta-Rigo, Margalida, Hrovat, Katja, Puigbò, Pere, Nakamura, Miho·2025·Communications Biology
DOI 10.1038/s42003-025-09292-1PMC PMC12780083

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Abstract

Abstract The skeleton supports the muscles in keeping the body upright against gravity while enduring thousands of daily loads. In this study, we investigated non-collagenous bone matrix proteins using osteoblast cell cultures and phylogenetic analyses to identify the molecular mechanisms involved in mechanical loading. The results indicate that the bone mechano-response is an evolutionary-driven process and that several non-collagenous proteins may significantly regulate the bone’s response to mechanical stress. According to our results, two significant evolutionary transitions in vertebrate locomotion shaped the roles of non-collagenous proteins in humans: the water-to-land transition, which increased mechanical stress on the limbs, and the evolution to bipedalism in humans, which altered the distribution of stress on the lower and upper limbs. Fetuin A, positively selected in both evolutionary transitions, showed the most significant expression change during mechanical stimulation.

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References 47 · Cited by 1

Research works printed but not linked: 47

  1. Ding, S. et al. Perception and response of skeleton to mechanical stress. Phys. Life Rev. 49, 77–94 (2024). · DOI
  2. Iolascon, G., Resmini, G. & Tarantino, U. Mechanobiology of bone. Aging Clin. Exp. Res. 25, S3–S7 (2013). · DOI
  3. Rolvien, T. et al. Long-term immobilization in elderly females causes a specific pattern of cortical bone and osteocyte deterioration different from postmenopausal osteoporosis. J. Bone Miner. Res. 35, 1343–1351 (2020). · DOI
  4. Baran, R. et al. Microgravity-related changes in bone density and treatment options: a systematic review. Int. J. Mol. Sci. 23, 8650 (2022). · DOI
  5. Polzonetti, V., Pucciarelli, S., Vincenzetti, S. & Polidori, P. Dietary intake of vitamin d from dairy products reduces the risk of osteoporosis. Nutrients 12, 1743 (2020). · DOI
  6. Pinheiro, M. B. et al. Evidence on physical activity and osteoporosis prevention for people aged 65+ years: a systematic review to inform the WHO guidelines on physical activity and sedentary behaviour. Int. J. Behav. Nutr. Phys. Act. 17, 150 (2020). · DOI
  7. Yan, Y., Wang, L., Ge, L. & Pathak, J. L. Osteocyte-mediated translation of mechanical stimuli to cellular signaling and its role in bone and non-bone-related clinical complications. Curr. Osteoporos. Rep. 18, 67–80 (2020). · DOI
  8. Wang, L. et al. Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat. Commun. 11, 282 (2020). · DOI
  9. Fujihara, S. et al. Function and regulation of osteopontin in response to mechanical stress. J. Bone Miner. Res. 21, 956–964 (2006). · DOI
  10. Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010). · DOI · Paper page
  11. Fontcuberta-Rigo, M., Nakamura, M. & Puigbò, P. Phylobone: a comprehensive database of bone extracellular matrix proteins in human and model organisms. Bone Res. 11, 44 (2023). · DOI
  12. Frost, H. M. Wolff’s Law and bone’s structural adaptations to mechanical usage: an overview for clinicians. Angle Orthod. 64, 175–188 (1994).
  13. Halperin, C. et al. Piezoelectric effect in human bones studied in nanometer scale. Nano Lett. 4, 1253–1256 (2004). · DOI
  14. Nakamura, M., Hiratai, R. & Yamashita, K. Bone mineral as an electrical energy reservoir. J. Biomed. Mater. Res. A 100, 1368–1374 (2012). · DOI
  15. MacIver, M. A. & Finlay, B. L. The neuroecology of the water-to-land transition and the evolution of the vertebrate brain. Philos. Trans. R. Soc. Lond. B Biol. Sci. 377, 20200523 (2022). · DOI
  16. Lovejoy, C. O., Suwa, G., Spurlock, L., Asfaw, B. & White, T. D. The pelvis and femur of Ardipithecus ramidus: the emergence of upright walking. Science 326, 71e1–76e1 (2009). · DOI
  17. Böhme, M. et al. A new Miocene ape and locomotion in the ancestor of great apes and humans. Nature 575, 489–493 (2019). · DOI
  18. Harcourt-Smith, W. H. E. The first hominins and the origins of bipedalism. Evol. Edu. Outreach 3, 333–340 (2010). · DOI
  19. Gans, C., Gaunt, A. S. & Webb, P. W. Vertebrate locomotion. In Comprehensive Physiology (ed. Prakash, Y. S.) 55–213 (Wiley, 2011). · DOI
  20. Vallender, E. J. & Lahn, B. T. Positive selection on the human genome. Hum. Mol. Genet. 13 Spec No 2, R245–R254 (2004). · DOI
  21. Cai, J. J. & Petrov, D. A. Relaxed purifying selection and possibly high rate of adaptation in primate lineage-specific genes. Genome Biol. Evol. 2, 393–409 (2010). · DOI
  22. Kawasaki, K., Buchanan, A. V. & Weiss, K. M. Gene duplication and the evolution of vertebrate skeletal mineralization. Cells Tissues Organs 186, 7–24 (2007). · DOI
  23. Cardoso-Moreira, M. et al. Evidence for the fixation of gene duplications by positive selection in Drosophila. Genome Res. 26, 787–798 (2016). · DOI
  24. Hopstaken, A. J. P., Große Wichtrup, E. & Jongkees, S. A. K. The great codon escape: vacating codons for genetic code expansion and ribosome stalling. Isr. J. Chem. 64, e202400012 (2024). · DOI
  25. Doherty, A. & McInerney, J. O. Translational selection frequently overcomes genetic drift in shaping synonymous codon usage patterns in vertebrates. Mol. Biol. Evol. 30, 2263–2267 (2013). · DOI
  26. Puigbò, P., Romeu, A. & Garcia-Vallvé, S. HEG-DB: a database of predicted highly expressed genes in prokaryotic complete genomes under translational selection. Nucleic Acids Res. 36, D524–D527 (2008). · DOI
  27. Sharp, P. M., Stenico, M., Peden, J. F. & Lloyd, A. T. Codon usage: mutational bias, translational selection, or both?. Biochem. Soc. Trans. 21, 835–841 (1993). · DOI
  28. Tanakas, S., Aubin, J. E. & van Wijnen, A. J. Epigenetic control of skeletal homeostasis and diseases. Bone 144, 115797 (2021). · DOI
  29. Klein-Nulend, J., Bakker, A. D., Bacabac, R. G., Vatsa, A. & Weinbaum, S. Mechanosensation and transduction in osteocytes. Bone 54, 182–190 (2013). · DOI · Paper page
  30. Shi, Y. & Massagué, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003). · DOI
  31. Tsukasaki, M. & Takayanagi, H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat. Rev. Immunol. 19, 626–642 (2019). · DOI
  32. Indjeian, V. B. et al. Evolving new skeletal traits by cis-regulatory changes in bone morphogenetic proteins. Cell 164, 45–56 (2016). · DOI
  33. Kan, C. et al. Fetuin-A is an immunomodulator and a potential therapeutic option in BMP4-dependent heterotopic ossification and associated bone mass loss. Bone Res. 10, 62 (2022). · DOI
  34. Jablonski, H. et al. A single intraperitoneal injection of bovine fetuin-A attenuates bone resorption in a murine calvarial model of particle-induced osteolysis. Bone 105, 262–268 (2017). · DOI
  35. Lin, X., Patil, S., Gao, Y.-G. & Qian, A. The bone extracellular matrix in bone formation and regeneration. Front. Pharmacol. 11, 757 (2020). · DOI
  36. Edgar, R. C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004). · DOI · Paper page
  37. Prlic, A. et al. Pre-calculated protein structure alignments at the RCSB PDB website. Bioinformatics 26, 2983–2985 (2010). · DOI
  38. Zhang, Y. & Skolnick, J. TM-align: a protein structure alignment algorithm based on the TM-score. Nucleic Acids Res. 33, 2302–2309 (2005). · DOI · Paper page
  39. Lemoine, F. et al. NGPhylogeny.fr: new generation phylogenetic services for non-specialists. Nucleic Acids Res. 47, W260–W265 (2019). · DOI
  40. Katoh, K. & Standley, D. M. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol. Biol. Evol. 30, 772–780 (2013). · DOI · Paper page
  41. Criscuolo, A. & Gribaldo, S. BMGE (Block Mapping and Gathering with Entropy): a new software for selection of phylogenetic informative regions from multiple sequence alignments. BMC Evol. Biol. 10, 210 (2010). · DOI
  42. Guindon, S. et al. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst. Biol. 59, 307–321 (2010). · DOI · Paper page
  43. Suyama, M., Torrents, D. & Bork, P. PAL2NAL: robust conversion of protein sequence alignments into the corresponding codon alignments. Nucleic Acids Res. 34, W609–W612 (2006). · DOI
  44. Birney, E., Thompson, J. D. & Gibson, T. J. PairWise and SearchWise: finding the optimal alignment in a simultaneous comparison of a protein profile against all DNA translation frames. Nucleic Acids Res. 24, 2730–2739 (1996). · DOI
  45. Nei, M. & Gojobori, T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol. Biol. Evol. 3, 418–426 (1986).
  46. Virtanen, P. et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat. Methods 17, 261–272 (2020). · DOI · Paper page
  47. Michael Delaine-Smith, R., Javaheri, B., Helen Edwards, J., Vazquez, M. & Rumney, R. M. H. Preclinical models for in vitro mechanical loading of bone-derived cells. Bonekey Rep. 4, 728 (2015). · DOI

Metadata

Authors
Shimochi, S., Brunet, C., Fontcuberta-Rigo, M., Hrovat, K., Puigbò, P., & Nakamura, M.
Affiliations
  • University of Turku (FI)
  • Universitat Autònoma de Barcelona (ES)
Corresponding author
  • Puigbò, Pere
  • Nakamura, Miho
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2025-11-29
Volume
9
Issue
1
Pages
31-31
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-025-09292-1
PMC
PMC12780083
OpenAlex
W4416821153
Cited by
1
References
47
Citations by year
2026: 1
FWCI
0.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • dCOBISS.SI Digital Repository (submittedVersion, cc-by-nc-nd)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-nd)
  • DiRROS repository (University of Maribor) (submittedVersion, cc-by-nc-nd)
  • UTUPub (University of Turku) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Sigrid Juséliuksen Säätiö (230131)
  • Murata Science Foundation (M20-072)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Bone and Dental Protein Studies
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Keywords
vertebrate evolution, locomotion evolution, water-to-land transition, bipedalism, fetuin-A, positive selection, osteoblasts, mechanical loading, osteogenic differentiation
MeSH terms
Animals, Biomechanical Phenomena, Bone and Bones, Biological Evolution, Humans, Locomotion, Osteoblasts, Phylogeny, Stress, Mechanical, Vertebrates

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