Next Article in Journal
Dual-Action Effect of Gallium and Silver Providing Osseointegration and Antibacterial Properties to Calcium Titanate Coatings on Porous Titanium Implants
Next Article in Special Issue
Lipopolysaccharide Impedes Bone Repair in FcγRIIB-Deficient Mice
Previous Article in Journal
Melatonin Role in Plant Growth and Physiology under Abiotic Stress
Previous Article in Special Issue
Exosomes Derived from Adipose Stem Cells Enhance Bone Fracture Healing via the Activation of the Wnt3a/β-Catenin Signaling Pathway in Rats with Type 2 Diabetes Mellitus
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Editorial

Bone Development and Regeneration 2.0

Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(10), 8761; https://doi.org/10.3390/ijms24108761
Submission received: 7 April 2023 / Revised: 29 April 2023 / Accepted: 4 May 2023 / Published: 15 May 2023
(This article belongs to the Special Issue Bone Development and Regeneration 3.0)
Bone is an important tissue which is a structural body component, carrying out the roles of mechanical stress response and organ/tissue protection. In addition, bone, as an integral organ, not only regulates bone metabolism and regulates the hematopoietic niche, but also acts as an endocrine organ to control some metabolic processes that are independent of bone metabolism.
Bone homeostasis is regulated and maintained by the remodeling cycle of osteoblastic bone formation and osteoclastic bone resorption [1,2]. When breaking the balance of bone homeostasis, bone remodeling cannot maintain an invariant bone mass, consequently leading to osteopenia and eventually osteoporosis [1,2,3,4]. Osteoporosis is an age-related common disease that is characterized by low bone mass and bone microstructural destruction resulting from the downregulation of bone remodeling and bone homeostasis [1,3,4]. In comparison with other organs/tissues, bone shows a high regenerative and remodeling potential throughout the human lifespan. Although bone tissue has a high regenerative and remodeling potential, this gradually decreases with age. Indeed, with the continual extension of life expectancy, aging-related bone mass loss and pathologies are increasing in a gradual manner, which negatively influences the quality of daily living of an increasing number of individuals. In particular, osteoporosis causes significant impacts on activities of daily living (ADL), which are expected to be further accentuated in future by the continuous increase in life expectancy. New scientific capabilities and perspectives are needed to further understand the mechanism of bone homeostasis.
Regarding bone metabolism, several mechanisms and pathways, such as the wingless-type (WNT)/beta-catenin, bone morphogenetic protein (BMP) 2 or parathyroid hormone (PTH) signaling pathways, have been thoroughly studied over the last few decades. Among numerous regulatory factors in bone metabolism, mechanical stress is recognized as a critically important factor in bone-associated cell differentiation/growth and their functions, including those of osteoblasts, osteoclasts and osteocytes [5,6,7]. Recent studies have demonstrated that physiologic mechanical loading stimulates osteoblast differentiation and resultant bone formation, and this is regulated by the molecular signaling pathway controlling osteocytes in response to mechanical stress [8,9,10]. Lin C. et al. demonstrated that osteocyte-produced sclerostin (in response to mechanical loading) controls the bone-remodeling cycle (bone formation and resorption) as a master molecule in mechano-transduction [11]. Mechanical-stress-mediated bone metabolism is realized through the interaction between two opponent mechanisms: (1) mechanical unloading accelerates sclerostin expression, which counteracts the Wnt/beta-catenin signaling pathway through the interaction between osteocytes and osteoblasts, allowing the concurrent Wnt-noncanonical pathway in osteocytes to osteoclasts, and is directed at bone resorption; on the contrary, (2) mechanical loading decreases the expression of sclerostin, inducing the activation of Wnt/beta-catenin signaling in osteocytes, consequently resulting in osteoblast differentiation and bone formation [11]. The interaction of osteoblasts with osteocytes through the osteocytic sclerostin-Wnt/beta-catenin signaling pathway is closely implicated in the mechanical-stress-mediated osteoblast differentiation following the acceleration of bone formation [8,9,10,11,12].
Conversely, a recent report clearly indicates that physiologic mechanical stress directly causes osteoblast differentiation and increased bone formation without a mechanism involving the Wnt/beta-catenin signaling pathway connecting osteocytes and osteoblasts as mentioned above [13]. Somemura S. et al. studied the interaction of the mechanical stress response with glucose metabolism via the glucose transporter (Glut)-1 and energy sensor sirtuin (Sirt)-1 in osteoblast energy metabolism [13]. They clearly revealed that both regulators of energy metabolism, Glut-1 and Sirt-1, also function as master molecules of stress responses against mechanical loading in osteoblasts. Mechanical loading to osteoblasts changed the expression of Glut-1 and Sirt-1 following the activation of the osteogenic transcription factor, Runx2, and resultant bone formation. Indeed, the inactivation of cell surface Glut-1 by the inhibitor significantly reduced the mechanical-loading-induced changes in the Sirt-1-to-Runx2 signaling pathway as well as bone formation activity, suggesting that the activation of Glut1 is required for mechanical-stress-mediated osteoblast differentiation and bone formation, via the signal transduction network between the energy sensor Sirt-1 and the osteogenic transcription factor Runx2, in osteoblasts. The Glu-1-Sirt-1-Runx2 pathway in osteoblasts may play some sort of role in mechanical-stress-mediated bone formation and osteoblast differentiation, without the osteocytic sclerostin−Wnt/beta-catenin signaling pathway. Mechanical loading may directly induce osteoblast differentiation and bone formation through the signaling pathway of glucose metabolism, without a sclerostin–Wnt/beta-catenin-dependent pathway through osteocyte-to-osteoblast contact. Indeed, it has been indicated that glucose uptake induces the osteoblast differentiation and bone formation potential by activating Runx2 activity in osteoblasts [14,15,16,17].
Attention has been attracted by recent findings that the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sirt-1 regulates many metabolic functions, such as inflammatory response, apoptosis, cell cycle, DNA repair, genome stability, mitochondrial function, cellular energy metabolism (adenosine triphosphate production) and cell responses to extrinsic stresses, including mechanical stress [18,19,20,21,22,23]. It has been also indicated that Sirt-1 has two important roles—“regulation of cell energy metabolism” and “response to cellular stresses (stress tolerance)”—which are involved in some metabolisms, and the pathogenesis and pathology of a variety of diseases, including mechanical-stress-induced degenerative diseases [24,25,26]. These findings provide evidence to support Sirt-1 activity being a key factor which links the mechanical stress response to energy metabolism in osteoblasts. In other words, the cell surface Glut-1-to-Sirt-1 pathway may have an important role as a mechano-sensor in osteoblasts. Further understanding of the mechanisms involved in the response of osteoblasts to mechanical stress is conducive to the elucidation of bone metabolism and the pathophysiology of osteoporosis.
In particular, several factors and proteins are linked to the regulatory mechanisms of bone development and growth, as well as bone regeneration and degeneration [27,28,29,30]. Saito M et al. indicated that 4.1 G, a plasma-membrane-associated cytoskeletal protein, promotes primary ciliogenesis in the differentiating preosteoblasts and induction of cilia-mediated osteoblast differentiation at the newborn stage [27]. Interestingly, it has been demonstrated that LIM-homeodomain transcription factor (Lmx1b), which plays a key role in body pattern formation during development, negatively regulates osteoblast differentiation and function through regulation of Runx2 [28]. Although further studies are needed to clarify the exact mechanism in bone biology, these papers will generate a representative picture of the latest advances in bone research and serve as a road map for where the field is headed.

Author Contributions

Conceptualization, K.Y., Y.S. and Y.S-T.; investigation, K.Y., Y.S. and Y.S.-T.; resources, K.Y.; writing—original draft preparation, K.Y.; writing—review and editing, Y.S. and Y.S.-T.; visualization, K.Y.; supervision, K.Y.; project administration, K.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Armas, L.A.; Recker, R.R. Pathophysiology of Osteoporosis: New Mechanistic Insights. Dev. Cell. 2008, 14, 661–673. [Google Scholar]
  2. Trüssel, A.; Müller, R.; Webster, D. Toward mechanical systems biology in bone. Ann. Biomed. Eng. 2012, 40, 2475–2487. [Google Scholar] [CrossRef] [PubMed]
  3. Coughlan, T.; Dockery, F. Osteoporosis and fracture risk in older people. Clin. Med. 2014, 14, 187–191. [Google Scholar] [CrossRef] [PubMed]
  4. Alford, A.I.; Kozloff, K.M.; Hankenson, K.D. Extracellular matrix networks in bone remodeling. Int. J. Biochem. Cell Biol. 2015, 65, 20–31. [Google Scholar] [CrossRef] [PubMed]
  5. Vergroesen, P.P.; Kingma, I.; Emanuel, K.S.; Hoogendoorn, R.J.; Welting, T.J.; van Royen, B.J.; van Dieën, J.H.; Smit, T.H. Mechanics and Biology in Intervertebral Disc Degeneration: A Vicious Circle. Osteoarthr. Cartil. 2015, 23, 1057–1070. [Google Scholar] [CrossRef] [PubMed]
  6. Yuan, Y.; Zhang, L.; Tong, X.; Zhang, M.; Zhao, Y.; Guo, J.; Lei, L.; Chen, X.; Tickner, J.; Xu, J.; et al. Mechanical Stress Regulates Bone Metabolism Through MicroRNAs. J. Cell. Physiol. 2017, 232, 1239–1245. [Google Scholar] [CrossRef]
  7. Maycas, M.; Esbrit, P.; Gortázar, A.R. Molecular mechanisms in bone mechanotransduction. Histol. Histopathol. 2017, 32, 751–760. [Google Scholar] [CrossRef] [PubMed]
  8. Sapir-Koren, R.; Livshits, G. Osteocyte control of bone remodeling: Is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles? Osteoporos. Int. 2014, 25, 2685–2700. [Google Scholar] [CrossRef]
  9. Uda, Y.; Azab, E.; Sun, N.; Shi, C.; Pajevic, P.D. Osteocyte Mechanobiology. Curr. Osteoporos. Rep. 2017, 15, 318–325. [Google Scholar] [CrossRef] [PubMed]
  10. Hinton, P.V.; Rackard, S.M.; Kennedy, O.D. In Vivo Osteocyte Mechanotransduction: Recent Developments and Future Directions. Curr. Osteoporos. Rep. 2018, 16, 746–753. [Google Scholar] [CrossRef] [PubMed]
  11. Lin, C.; Jiang, X.; Dai, Z.; Guo, X.; Weng, T.; Wang, J.; Li, Y.; Feng, G.; Gao, X.; He, L. Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/beta-catenin Signaling. J. Bone Miner. Res. 2009, 24, 1651–1661. [Google Scholar] [CrossRef] [PubMed]
  12. Galea, G.L.; Lanyon, L.E.; Price, J.S. Sclerostin’s Role in Bone’s Adaptive Response to Mechanical Loading. Bone 2017, 96, 38–44. [Google Scholar] [CrossRef] [PubMed]
  13. Somemura, S.; Kumai, T.; Yatabe, K.; Sasaki, C.; Fujiya, H.; Niki, H.; Yudoh, K. Physiologic Mechanical Stress Directly Induces Bone Formation by Activating Glucose Transporter 1 (Glut 1) in Osteoblasts, Inducing Signaling via NAD+-Dependent Deacetylase (Sirtuin 1) and Runt-Related Transcription Factor 2 (Runx2). Int. J. Mol. Sci. 2021, 22, 9070. [Google Scholar] [CrossRef] [PubMed]
  14. Wei, J.; Shimazu, J.; Makinistoglu, M.P.; Maurizi, A.; Kajimura, D.; Zong, H.; Takarada, T.; Lezaki, T.; Pes-sin, J.E.; Hinoi, E.; et al. Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation. Cell 2015, 161, 1576–1591. [Google Scholar] [CrossRef]
  15. Dirckx, N.; Tower, R.J.; Mercken, E.M.; Vangoitsenhoven, R.; Moreau-Triby, C.; Breugelmans, T.; Nefyodova, E.; Cardoen, R.; Mathieu, C.; Van der Schueren, B.; et al. Vhl deletion in osteoblasts boosts cellular glycolysis and im-proves global glucose metabolism. J. Clin. Investig. 2018, 128, 1087–1105. [Google Scholar] [CrossRef]
  16. Karvande, A.; Kushwaha, P.; Ahmad, N.; Adhikary, S.; Kothari, P.; Tripathi, A.K.; Khedgikar, V.; Trivedi, R. Glucose dependent miR-451a expression contributes to parathyroid hormone mediated osteoblast differentiation. Bone 2018, 117, 98–115. [Google Scholar] [CrossRef]
  17. Li, W.; Deng, Y.; Feng, B.; Mak, K.K. Mst1/2 Kinases Modulate Glucose Uptake for Osteoblast Differentiation and Bone Formation. J. Bone 28-Miner. Res. 2018, 33, 1183–1195. [Google Scholar] [CrossRef]
  18. Bordone, L.; Guarente, L. Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nat. Rev. Mol. Cell Biol. 2005, 6, 298–305. [Google Scholar] [CrossRef]
  19. Haigis, M.C.; Guarente, L.P. Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006, 20, 2913–2921. [Google Scholar] [CrossRef]
  20. Guarente, L. Sirtuins, aging, and metabolism. Cold Spring Harb. Symp. Quant. Biol. 2011, 76, 81–90. [Google Scholar] [CrossRef]
  21. Mouchiroud, L.; Houtkooper, R.H.; Moullan, N.; Katsyuba, E.; Ryu, D.; Cantó, C.; Mottis, A.; Jo Young-Suk Viswanathan, M.; Schoonjans, K.; Guarente, L.; et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 2013, 154, 430–441. [Google Scholar] [CrossRef] [PubMed]
  22. Imai, S.-I.; Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014, 24, 464–471. [Google Scholar] [CrossRef]
  23. Wątroba, M.; Szukiewicz, D. The role of sirtuins in aging and age-related diseases. Adv. Med Sci. 2016, 61, 52–62. [Google Scholar] [CrossRef] [PubMed]
  24. Chen, Z.; Peng, I.C.; Cui, X.; Li, Y.S.; Chien, S.; Shyy, J.Y. Shear Stress, SIRT1, and Vascular Homeostasis. Proc. Natl. Acad. Sci. USA 2010, 107, 10268–10273. [Google Scholar] [CrossRef] [PubMed]
  25. Lee, S.I.; Park, K.H.; Kim, S.J.; Kang, Y.G.; Lee, Y.M.; Kim, E.C. Mechanical stress-activated immune response genes via Sirtuin 1 expression in human periodontal ligament cells. Clin. Exp. Immunol. 2012, 168, 113–124. [Google Scholar] [CrossRef]
  26. Liu, J.; Bi, X.; Chen, T.; Zhang, Q.; Wang, S.X.; Chiu, J.J.; Liu, G.S.; Zhang, Y.; Bu, P.; Jiang, F. Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression. Cell Death Dis. 2015, 6, e1827. [Google Scholar] [CrossRef]
  27. Saito, M.; Hirano, M.; Izumi, T.; Mori, Y.; Ito, K.; Saitoh, Y.; Terada, N.; Sato, T.; Sukegawa, J. Cytoskeletal Protein 4.1G Is Essential for the Primary Ciliogenesis and Osteoblast Differentiation in Bone Formation. Int. J. Mol. Sci. 2022, 23, 2094. [Google Scholar] [CrossRef]
  28. Kim, K.; Kim, J.H.; Kim, I.; Seong, S.; Han, J.E.; Lee, K.B.; Koh, J.T.; Kim, N. Transcription Factor Lmx1b Negatively Regulates Osteo-blast Differentiation and Bone Formation. Int. J. Mol. Sci. 2022, 23, 5225. [Google Scholar] [CrossRef]
  29. Franko, N.; Vrščaj, L.A.; Zore, T.; Ostanek, B.; Marc, J.; Lojk, J. TBP, PPIA, YWHAZ and EF1A1 Are the Most Stably Expressed Genes during Osteogenic Differentiation. Int. J. Mol. Sci. 2022, 23, 4257. [Google Scholar] [CrossRef]
  30. Morsczeck, C. Mechanisms during Osteogenic Differentiation in Human Dental Follicle Cells. Int. J. Mol. Sci. 2022, 23, 5945. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Yudoh, K.; Sugishita, Y.; Suzuki-Takahashi, Y. Bone Development and Regeneration 2.0. Int. J. Mol. Sci. 2023, 24, 8761. https://doi.org/10.3390/ijms24108761

AMA Style

Yudoh K, Sugishita Y, Suzuki-Takahashi Y. Bone Development and Regeneration 2.0. International Journal of Molecular Sciences. 2023; 24(10):8761. https://doi.org/10.3390/ijms24108761

Chicago/Turabian Style

Yudoh, Kazuo, Yodo Sugishita, and Yuki Suzuki-Takahashi. 2023. "Bone Development and Regeneration 2.0" International Journal of Molecular Sciences 24, no. 10: 8761. https://doi.org/10.3390/ijms24108761

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop