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Wahnou, H. Hypoxia's Influence on Bone Remodeling Molecular Pathways. Encyclopedia. Available online: https://encyclopedia.pub/entry/48774 (accessed on 08 September 2024).
Wahnou H. Hypoxia's Influence on Bone Remodeling Molecular Pathways. Encyclopedia. Available at: https://encyclopedia.pub/entry/48774. Accessed September 08, 2024.
Wahnou, Hicham. "Hypoxia's Influence on Bone Remodeling Molecular Pathways" Encyclopedia, https://encyclopedia.pub/entry/48774 (accessed September 08, 2024).
Wahnou, H. (2023, September 04). Hypoxia's Influence on Bone Remodeling Molecular Pathways. In Encyclopedia. https://encyclopedia.pub/entry/48774
Wahnou, Hicham. "Hypoxia's Influence on Bone Remodeling Molecular Pathways." Encyclopedia. Web. 04 September, 2023.
Hypoxia's Influence on Bone Remodeling Molecular Pathways
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Bone remodeling is a crucial physiological process for maintaining skeletal health. It focuses on the central roles of osteoblasts, osteoclasts, and osteocytes, as well as the composition of the bone's extracellular matrix. Furthermore, it explores the impact of hypoxia, or low oxygen levels, on bone health and elucidates the responsible molecular mechanisms. While bone remodeling units (BMUs), their cellular components, and the phases of the remodeling cycle remain not fully understood, the text also addresses systemic and local factors, including the critical RANK-RANKL-OPG pathway, that govern bone remodeling. This contributes to a comprehensive understanding of this intricate biological process.

hypoxia Bone remodeling osteoclat osteoblast osteocyte Bone Remodeling Vitamin D

1. Introduction

Bone is a highly dynamic tissue that undergoes continuous remodeling to maintain skeletal health and strength. This remodeling process allows bones to adapt to various functional demands while serving essential functions such as supporting muscles, protecting vital organs, and storing calcium and phosphorus for metabolic processes [1]. The primary cellular components responsible for bone health are osteoblasts, osteoclasts, and osteocytes [1][2]. Bone's extracellular matrix comprises a mineral component, mainly hydroxyapatite, and an organic component, primarily collagen, along with non-collagenous proteins like sialoprotein, osteonectin, osteopontin, and osteocalcin. Mature bone can be classified into two histological types: cortical, which is dense and compact, accounting for 80% of total bone mass, and trabecular, which is lighter and less compact with an irregular structure [1][3].

Sufficient oxygen availability is of paramount importance to uphold the efficient functioning of cells and tissues. In instances where cells encounter an insufficiency of oxygen, termed hypoxia, they undergo intricate molecular and physiological adaptations to safeguard their viability[4]. Hypoxia can exert a significant impact on the intricate framework of bone health, disrupting the delicate equilibrium of bone remodeling processes [3].This interplay between oxygen levels and bone homeostasis underscores the intricate relationship between tissue oxygenation and skeletal integrity.

1. Bone Remodeling and Cells Involved

Bone remodeling is a precisely regulated process that occurs within specialized units known as bone remodeling units (BMUs). These BMUs comprise four principal cell types: bone lining cells, osteocytes, osteoclasts, and osteoblasts. Osteocytes, which are mature osteoblasts embedded within the bone matrix, play a pivotal role in detecting areas of skeletal weakness and orchestrating remodeling. Osteoclasts are responsible for bone resorption, while osteoblasts contribute to bone formation [5].

The bone remodeling cycle consists of several phases, including initiation, resorption, reversal, formation, and mineralization, each finely tuned by systemic factors such as parathyroid hormone and local regulators like growth factors and cytokines. Additionally, the RANK-RANKL-OPG pathway plays a crucial role in regulating bone remodeling [6][7].

Hypoxia on the other hand, is characterized by insufficient oxygen levels, can profoundly affect bone cell activity and remodeling. This review explores the impact of hypoxia on the main bone remodeling cells and their associated molecular pathways.

1.1. Osteocytes

Osteocytes, derived from osteoblasts, are multifunctional cells embedded within the mineralized bone matrix. They play essential roles in regulating bone metabolism, acting as mechanosensors to detect and respond to mechanical stresses. Osteocytes produce sclerostin, a protein that inhibits bone formation by blocking the Wnt pathway. Additionally, osteocytes can stimulate bone resorption through RANKL secretion or inhibit it by producing OPG, which competes with RANKL [8][9].

1.2. Osteoclasts

Osteoclasts are specialized cells responsible for bone resorption. They differentiate from precursor cells and are regulated by various factors, including RANKL and macrophage colony-stimulating factor (M-CSF) [10]. Osteoclasts adhere to bone surfaces, create resorption gaps, and release hydrogen ions to acidify the environment, facilitating the degradation of bone matrix [11]. They also reabsorb detached materials, such as collagen and calcium. Osteoclast activation is a prerequisite for osteoblast activation, and this crosstalk is critical in bone remodeling [12].

1.3. Osteoblasts

Osteoblasts originate from mesenchymal progenitors and are involved in bone matrix formation and mineralization [13]. Transcription factors like Runx2, Sox9, and Atf-4 regulate osteoblast differentiation and maturation. Various growth factors, including TGF-β, IGF-1, and FGF, activate signaling pathways that influence osteoblast function. Osteoblasts are vital for bone formation and maintenance [12][14].

2. Hypoxia: Local Effects on Bone Metabolism Cells

Hypoxia, characterized by low oxygen levels, triggers cellular responses mediated by hypoxia-inducible factors (HIFs). HIFs consist of oxygen-sensitive HIF-α subunits and constitutively expressed HIF-β subunits [15]. Under hypoxia, HIF-α accumulates and translocates to the nucleus, where it activates the expression of over 200 genes involved in survival mechanisms [16].

In bone tissue, which typically experiences oxygen levels around 6.6-8.5%, hypoxia can significantly impact bone cell function [17]. Hypoxia has been associated with reduced osteoblast differentiation and activity, delayed growth, and impaired matrix mineralization [18]. Conversely, it promotes osteoclastogenesis and enhances osteoclast resorptive capacity. These effects are mediated by various molecular pathways, including HIF-1α and HIF-2α [20].

3. Hypoxia, Erythropoietin, and Bone Remodeling

Erythropoietin (EPO) is a hormone produced in response to hypoxia, stimulating red blood cell production [21]. EPO and its receptor (EPO-R) are also found in bone tissue, suggesting a potential role in bone metabolism [22]. EPO appears to have complex effects on bone, with some studies indicating that it stimulates osteogenesis through various signaling pathways, while others suggest it may lead to increased bone resorption [23][24]. EPO's influence on bone cells and its role in hypoxia-induced bone remodeling require further investigation [25].

4. Vitamin D Metabolism, Inflammation, Hypoxia, and Bone

Vitamin D is essential for calcium and phosphorus metabolism, cell proliferation, and immune system regulation [26]. The vitamin D receptor (VDR) mediates its effects when activated by calcitriol [26]. Hypoxia-induced inflammation, characterized by increased cytokine production, can activate NF-κB signaling [27]. Vitamin D has been shown to inhibit NF-κB pathway activation in immune cells and osteoclasts, suggesting a potential role in modulating the bone response to hypoxia [28].

5. Hypoxia and Bone Remodeling in Clinical Studies

Clinical studies investigating the effects of chronic hypoxia on bone metabolism in humans have yielded contradictory results  [8][29][30]. Long-term exposure to sustained hypoxia has been associated with reduced bone health, while short exposures may not produce significant alterations [31]. Conditions like obstructive sleep apnea syndrome, characterized by intermittent hypoxia, have been linked to changes in bone remodeling markers, but the underlying mechanisms are complex and not fully understood.

6. Conclusion

Hypoxia-driven changes in bone remodeling are intricate, involving complex molecular pathways. They affect bone cell differentiation and activity, potentially impacting bone formation and resorption. Factors such as EPO, vitamin D, and inflammation's role in modulating bone's response to hypoxia warrant deeper exploration. Clinical studies on chronic hypoxia's effects on human bone health offer conflicting results, underscoring the need for further research. Unraveling the molecular mechanisms behind hypoxia-induced bone remodeling is crucial for devising strategies to counter its negative impacts on skeletal well-being.

References

  1. Ralston, S.H. Bone structure and metabolism. Medicine 2013, 41, 581-585.
  2. Carvalho MS, Poundarik AA, Cabral JMS, da Silva CL, Vashishth D. Biomimetic matrices for rapidly forming mineralized bone tissue based on stem cell-mediated osteogenesis. Sci Rep. 2018 Sep 26;8(1):14388. doi: 10.1038/s41598-018-32794-4. PMID: 30258220; PMCID: PMC6158243.
  3. Florencio-Silva R, Sasso GR, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int. 2015;2015:421746. doi: 10.1155/2015/421746. Epub 2015 Jul 13. PMID: 26247020; PMCID: PMC4515490.
  4. Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol. 2020 May;21(5):268-283. doi: 10.1038/s41580-020-0227-y. Epub 2020 Mar 6. PMID: 32144406; PMCID: PMC7222024.
  5. Sims, N.A.; Martin, T.J. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BoneKEy reports 2014, 3, 481, doi:10.1038/bonekey.2013.215.
  6. Hadjidakis, D.J.; Androulakis, II. Bone remodeling. Annals of the New York Academy of Sciences 2006, 1092, 385-396, doi:10.1196/annals.1365.035.
  7. Siddiqui, J.A.; Partridge, N.C. Physiological Bone Remodeling: Systemic Regulation and Growth Factor Involvement. Physiology (Bethesda, Md.) 2016, 31, 233-245, doi:10.1152/physiol.00061.2014.
  8. Dallas, S.L.; Prideaux, M.; Bonewald, L.F. The osteocyte: an endocrine cell ... and more. Endocrine reviews 2013, 34, 658-690, doi:10.1210/er.2012-1026.
  9. Bonewald, L.F.; Johnson, M.L. Osteocytes, mechanosensing and Wnt signaling. Bone 2008, 42, 606-615, doi:10.1016/j.bone.2007.12.224.
  10. Boyce, B.F.; Xing, L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Archives of biochemistry and biophysics 2008, 473, 139-146.
  11. Henriksen, K.; Bollerslev, J.; Everts, V.; Karsdal, M.A. Osteoclast activity and subtypes as a function of physiology and pathology--implications for future treatments of osteoporosis. Endocrine reviews 2011, 32, 31-63, doi:10.1210/er.2010-0006.
  12. Long, F. Building strong bones: molecular regulation of the osteoblast lineage. Nature reviews. Molecular cell biology 2011, 13, 27-38, doi:10.1038/nrm3254.
  13. Dirckx, N.; Moorer, M.C.; Clemens, T.L.; Riddle, R.C. The role of osteoblasts in energy homeostasis. Nature Reviews Endocrinology 2019, 15, 651-665.
  14. Marie, P.J. Fibroblast growth factor signaling controlling bone formation: an update. Gene 2012, 498, 1-4, doi:10.1016/j.gene.2012.01.086.
  15. Zepeda, A.B.; Pessoa, A., Jr.; Castillo, R.L.; Figueroa, C.A.; Pulgar, V.M.; Farías, J.G. Cellular and molecular mechanisms in the hypoxic tissue: role of HIF-1 and ROS. Cell biochemistry and function 2013, 31, 451-459, doi:10.1002/cbf.2985.
  16. Kaluz, S.; Kaluzová, M.; Stanbridge, E.J. Rational design of minimal hypoxia-inducible enhancers. Biochem Biophys Res Commun 2008, 370, 613-618, doi:10.1016/j.bbrc.2008.03.147.
  17. Harrison, J.S.; Rameshwar, P.; Chang, V.; Bandari, P. Oxygen saturation in the bone marrow of healthy volunteers. Blood 2002, 99, 394, doi:10.1182/blood.v99.1.394.
  18. Utting, J.C.; Robins, S.P.; Brandao-Burch, A.; Orriss, I.R.; Behar, J.; Arnett, T.R. Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts. Experimental cell research 2006, 312, 1693-1702.
  19. Utting, J.C.; Robins, S.P.; Brandao-Burch, A.; Orriss, I.R.; Behar, J.; Arnett, T.R. Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts. Exp Cell Res 2006, 312, 1693-1702, doi:10.1016/j.yexcr.2006.02.007.
  20. Knowles, H.J. Distinct roles for the hypoxia-inducible transcription factors HIF-1α and HIF-2α in human osteoclast formation and function. Scientific reports 2020, 10, 21072, doi:10.1038/s41598-020-78003-z.
  21. Jelkmann, W. Regulation of erythropoietin production. The Journal of physiology 2011, 589, 1251-1258.
  22. Oikonomidou, P.R.; Casu, C.; Yang, Z.; Crielaard, B.; Shim, J.H.; Rivella, S.; Vogiatzi, M.G. Polycythemia is associated with bone loss and reduced osteoblast activity in mice. Osteoporosis International 2016, 27, 1559-1568.
  23. Rölfing, J.H.; Baatrup, A.; Stiehler, M.; Jensen, J.; Lysdahl, H.; Bünger, C. The osteogenic effect of erythropoietin on human mesenchymal stromal cells is dose-dependent and involves non-hematopoietic receptors and multiple intracellular signaling pathways. Stem cell reviews and reports 2014, 10, 69-78, doi:10.1007/s12015-013-9476-x.
  24. Hiram-Bab, S.; Neumann, D.; Gabet, Y. Erythropoietin in bone - Controversies and consensus. Cytokine 2017, 89, 155-159, doi:10.1016/j.cyto.2016.01.008.
  25. Hiram‐Bab, S.; Liron, T.; Deshet‐Unger, N.; Mittelman, M.; Gassmann, M.; Rauner, M.; Franke, K.; Wielockx, B.; Neumann, D.; Gabet, Y. Erythropoietin directly stimulates osteoclast precursors and induces bone loss. The FASEB journal 2015, 29, 1890-1900.
  26. Haussler, M.R.; Whitfield, G.K.; Kaneko, I.; Haussler, C.A.; Hsieh, D.; Hsieh, J.-C.; Jurutka, P.W. Molecular mechanisms of vitamin D action. Calcified tissue international 2013, 92, 77-98.
  27. Rius, J.; Guma, M.; Schachtrup, C.; Akassoglou, K.; Zinkernagel, A.S.; Nizet, V.; Johnson, R.S.; Haddad, G.G.; Karin, M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 2008, 453, 807-811, doi:10.1038/nature06905.
  28. Ge, X.; Wang, L.; Li, M.; Xu, N.; Yu, F.; Yang, F.; Li, R.; Zhang, F.; Zhao, B.; Du, J. Vitamin D/VDR signaling inhibits LPS-induced IFNγ and IL-1β in Oral epithelia by regulating hypoxia-inducible factor-1α signaling pathway. Cell communication and signaling : CCS 2019, 17, 18, doi:10.1186/s12964-019-0331-9.
  29. Basu, M.; Malhotra, A.S.; Pal, K.; Chatterjee, T.; Ghosh, D.; Haldar, K.; Verma, S.K.; Kumar, S.; Sharma, Y.K.; Sawhney, R.C. Determination of bone mass using multisite quantitative ultrasound and biochemical markers of bone turnover during residency at extreme altitude: a longitudinal study. High altitude medicine & biology 2013, 14, 150-154, doi:10.1089/ham.2012.1042.
  30. Basu, M.; Malhotra, A.S.; Pal, K.; Kumar, R.; Bajaj, R.; Verma, S.K.; Ghosh, D.; Sharma, Y.K.; Sawhney, R.C. Alterations in different indices of skeletal health after prolonged residency at high altitude. High altitude medicine & biology 2014, 15, 170-175, doi:10.1089/ham.2013.1098.
  31. Rittweger, J.; Debevec, T.; Frings-Meuthen, P.; Lau, P.; Mittag, U.; Ganse, B.; Ferstl, P.G.; Simpson, E.J.; Macdonald, I.A.; Eiken, O.; et al. On the combined effects of normobaric hypoxia and bed rest upon bone and mineral metabolism: Results from the PlanHab study. Bone 2016, 91, 130-138, doi:10.1016/j.bone.2016.07.013.
  32. Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol. 2020 May;21(5):268-283. doi: 10.1038/s41580-020-0227-y. Epub 2020 Mar 6. PMID: 32144406; PMCID: PMC7222024.
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