Decoding Cold Therapy Mechanisms of Enhanced Bone Repair through Sensory Receptors and Molecular Pathways
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cortical Defect Animal Model
2.2. Hypoxyprobe Treatments
2.3. Tissue Harvesting and Staining Analysis
2.4. Femoral Fracture Animal Model
2.5. Treatments and Cell Study
2.6. Statistical Design and Analysis
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Morgan, R.; Kalbarczyk, A.; Mohan, D.; Jacobs, C.; Mishra, M.; Tyagi, P.; Cox-Roman, C.; Williamson, C. Counting older women: Measuring the health and wellbeing of older women in LMICs. Cell Rep. Med. 2024, 5, 101607. [Google Scholar] [CrossRef] [PubMed]
- Zakaria, M.; Allard, J.; Garcia, J.; Matta, J.; Honjol, Y.; Schupbach, D.; Grant, M.; Mwale, F.; Harvey, E.; Merle, G. Enhancing Bone Healing Through Localized Cold Therapy in a Murine Femoral Fracture Model. Tissue Eng. Part A 2024. [Google Scholar] [CrossRef]
- Castano, D.; Comeau-Gauthier, M.; Ramirez-GarciaLuna, J.L.; Drager, J.; Harvey, E.; Merle, G. Noninvasive Localized Cold Therapy: A New Mode of Bone Repair Enhancement. Tissue Eng Part A 2019, 25, 554–562. [Google Scholar] [CrossRef]
- Du, J.; He, Z.; Cui, J.; Li, H.; Xu, M.; Zhang, S.; Zhang, S.; Yan, M.; Qu, X.; Yu, Z. Osteocyte Apoptosis Contributes to Cold Exposure-induced Bone Loss. Front. Bioeng. Biotechnol. 2021, 9, 733582. [Google Scholar] [CrossRef] [PubMed]
- Tanaka, T.; Wakamatsu, T.; Daijo, H.; Oda, S.; Kai, S.; Adachi, T.; Kizaka-Kondoh, S.; Fukuda, K.; Hirota, K. Persisting mild hypothermia suppresses hypoxia-inducible factor-1α protein synthesis and hypoxia-inducible factor-1-mediated gene expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010, 298, R661–R671. [Google Scholar] [CrossRef]
- Janský, L.; Pospíšilová, D.; Honzová, S.; Uličný, B.; Šrámek, P.; Zeman, V.; Kamínková, J. Immune system of cold-exposed and cold-adapted humans. Eur. J. Appl. Physiol. Occup. Physiol. 1996, 72, 445–450. [Google Scholar] [CrossRef]
- Gregson, W.; Black, M.A.; Jones, H.; Milson, J.; Morton, J.; Dawson, B.; Atkinson, G.; Green, D.J. Influence of Cold Water Immersion on Limb and Cutaneous Blood Flow at Rest. Am. J. Sports Med. 2011, 39, 1316–1323. [Google Scholar] [CrossRef] [PubMed]
- Fowler, E.P., Jr.; Osmun, P.M. New bone growth due to cold water in the ears. Arch. Otolaryngol. 1942, 36, 455–466. [Google Scholar] [CrossRef]
- White, G.E.; Wells, G.D. Cold-water immersion and other forms of cryotherapy: Physiological changes potentially affecting recovery from high-intensity exercise. Extrem. Physiol. Med. 2013, 2, 26. [Google Scholar] [CrossRef]
- Iommarini, L.; Porcelli, A.M.; Gasparre, G.; Kurelac, I. Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer. Front. Oncol. 2017, 7, 286. [Google Scholar] [CrossRef]
- Duvall, C.L.; Taylor, W.R.; Weiss, D.; Wojtowicz, A.M.; Guldberg, R.E. Impaired angiogenesis, early callus formation, and late stage remodeling in fracture healing of osteopontin-deficient mice. J. Bone Miner. Res. 2007, 22, 286–297. [Google Scholar] [CrossRef]
- Coassin, M.; Duncan, K.G.; Bailey, K.R.; Singh, A.; Schwartz, D.M. Hypothermia reduces secretion of vascular endothelial growth factor by cultured retinal pigment epithelial cells. Br. J. Ophthalmol. 2010, 94, 1678–1683. [Google Scholar] [CrossRef]
- Leegwater, N.C.; Bakker, A.D.; Hogervorst, J.M.A.; Nolte, P.A.; Klein-Nulend, J. Hypothermia reduces VEGF-165 expression, but not osteogenic differentiation of human adipose stem cells under hypoxia. PLoS ONE 2017, 12, e0171492. [Google Scholar] [CrossRef] [PubMed]
- Mohd Din, A.; Nor-Ashikin, M.N.K.; Ab Rahim, S.; Nawawi, H.; Kapitonova, M.; Froemming, G. Short-term moderate hypothermia stimulates alkaline phosphatase activity and osteocalcin expression in osteoblasts by upregulating Runx2 and osterix in vitro. Exp. Cell Res. 2014, 326, 46–56. [Google Scholar]
- Kim, J.C.; Yi, H.K.; Hwang, P.H.; Yoon, J.S.; Kim, H.J.; Kawano, F.; Ohira, Y.; Kim, C.K. Effects of cold-water immersion on VEGF mRNA and protein expression in heart and skeletal muscles of rats. Acta Physiol. Scand. 2005, 183, 389–397. [Google Scholar] [CrossRef]
- Xue, Y.; Petrovic, N.; Cao, R.; Larsson, O.; Lim, S.; Chen, S.; Feldmann, H.M.; Liang, Z.; Zhu, Z.; Nedergaard, J.; et al. Hypoxia-Independent Angiogenesis in Adipose Tissues during Cold Acclimation. Cell Metab. 2009, 9, 99–109. [Google Scholar] [CrossRef]
- Shakurov, A.V.; Lukina, Y.u.S.; Skriabin, A.S.; Bionyshev-Abramov, L.L.; Serejnikova, N.B.; Smolencev, D.V. Enhanced bone healing using local cryostimulation: In vivo rat study. J. Therm. Biol. 2023, 113, 103501. [Google Scholar] [CrossRef] [PubMed]
- Ihsan, M.; Abbiss, C.R.; Allan, R. Adaptations to Post-exercise Cold Water Immersion: Friend, Foe, or Futile? Front. Sports Act. Living 2021, 3, 714148. [Google Scholar] [CrossRef]
- Lindquist, J.A.; Mertens, P.R. Cold shock proteins: From cellular mechanisms to pathophysiology and disease. Cell Commun. Signal. 2018, 16, 63. [Google Scholar] [CrossRef]
- Muhlig Nielsen, M.; Overgaard, J.; Sørensen, J.G.; Holmstrup, M.; Justesen, J.; Loeschcke, V. Role of HSF activation for resistance to heat, cold and high-temperature knock-down. J. Insect Physiol. 2005, 51, 1320–1329. [Google Scholar] [CrossRef]
- Chen, H.; Fan, W.; He, H.; Huang, F. PGC-1: A key regulator in bone homeostasis. J. Bone Miner. Metab. 2022, 40, 1–8. [Google Scholar] [CrossRef]
- Hu, Y.; Liu, Y.; Quan, X.; Fan, W.; Xu, B.; Li, S. RBM3 is an outstanding cold shock protein with multiple physiological functions beyond hypothermia. J. Cell Physiol. 2022, 237, 3788–3802. [Google Scholar] [CrossRef] [PubMed]
- Puigserver, P.; Wu, Z.; Park, C.W.; Graves, R.; Wright, M.; Spiegelman, B.M. A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis. Cell 1998, 92, 829–839. [Google Scholar] [CrossRef] [PubMed]
- Oryan, A.; Monazzah, S.; Bigham-Sadegh, A. Bone Injury and Fracture Healing Biology. Biomed. Environ. Sci. 2015, 28, 57–71. [Google Scholar] [PubMed]
- Szczęsny, G. Fracture Repair: Its Pathomechanism and Disturbances. In Trauma Surgery; Karcioglu, O., Topacoglu, H., Eds.; IntechOpen: Rijeka, Croatia, 2018; Chapter 1. [Google Scholar] [CrossRef]
- Schoutens, A.; Bergmann, P.; Verhas, M. Bone blood flow measured by 85 Sr microspheres and bone seeker clearances in the rat. Am. J. Physiol. 1979, 236, H1–H6. [Google Scholar] [CrossRef]
- Pan, Y.; Thapa, D.; Baldissera, L.; Argunhan, F.; Aubdool, A.A.; Brain, S.D. Relevance of TRPA1 and TRPM8 channels as vascular sensors of cold in the cutaneous microvasculature. Pflügers Arch. Eur. J. Physiol. 2018, 470, 779–786. [Google Scholar] [CrossRef]
- Lieben, L.; Carmeliet, G. The Involvement of TRP Channels in Bone Homeostasis. Front. Endocrinol. 2012, 3, 99. [Google Scholar] [CrossRef]
- Earley, S.; Brayden, J.E. Transient receptor potential channels in the vasculature. Physiol. Rev. 2015, 95, 645–690. [Google Scholar] [CrossRef]
- McKemy, D.D. The molecular and cellular basis of cold sensation. ACS Chem. Neurosci. 2013, 4, 238–247. [Google Scholar] [CrossRef]
- Aubdool, A.A.; Graepel, R.; Kodji, X.; Alawi, K.M.; Bodkin, J.V.; Srivastava, S.; Gentry, C.; Heads, R.; Grant, A.D.; Fernandes, E.S.; et al. TRPA1 is essential for the vascular response to environmental cold exposure. Nat. Commun. 2014, 5, 5732. [Google Scholar] [CrossRef]
- Ali, E.; Birch, M.; Hopper, N.; Rushton, N.; McCaskie, A.W.; Brooks, R.A. Human osteoblasts obtained from distinct periarticular sites demonstrate differences in biological function in vitro. Bone Jt. Res. 2021, 10, 611–618. [Google Scholar] [CrossRef]
- Dey, P.; Rajalaxmi, S.; Saha, P.; Thakur, P.S.; Hashmi, M.A.; Lal, H.; Saini, N.; Singh, N.; Ramanathan, A. Cold-shock proteome of myoblasts reveals role of RBM3 in promotion of mitochondrial metabolism and myoblast differentiation. Commun. Biol. 2024, 7, 515. [Google Scholar] [CrossRef]
- Xu, L.; Ma, X.; Bagattin, A.; Mueller, E. The transcriptional coactivator PGC1α protects against hyperthermic stress via cooperation with the heat shock factor HSF1. Cell Death Dis. 2016, 7, e2102. [Google Scholar] [CrossRef]
- Krock, B.L.; Skuli, N.; Simon, M.C. Hypoxia-induced angiogenesis: Good and evil. Genes Cancer 2011, 2, 1117–1133. [Google Scholar] [CrossRef]
- Thapa, D.; de Valente, J.S.; Barrett, B.; Smith, M.J.; Argunhan, F.; Lee, S.Y.; Nikitochkina, S.; Kodji, X.; Brain, S.D. Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing. eLife 2021, 10, e70153. [Google Scholar] [CrossRef]
- Arteel, G.E.; Thurman, R.G.; Raleigh, J.A. Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state. Eur. J. Biochem. 1998, 253, 743–750. [Google Scholar] [CrossRef]
- Abhinand, C.S.; Raju, R.; Soumya, S.J.; Arya, P.S.; Sudhakaran, P.R. VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis. J. Cell. Commun. Signal 2016, 10, 347–354. [Google Scholar] [CrossRef]
- Wang, X.; Bove, A.M.; Simone, G.; Ma, B. Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role. Front. Cell Dev. Biol. 2020, 8, 599281. Available online: https://www.frontiersin.org/articles/10.3389/fcell.2020.599281 (accessed on 12 June 2024). [CrossRef]
- Negri, S.; Faris, P.; Berra-Romani, R.; Guerra, G.; Moccia, F. Endothelial Transient Receptor Potential Channels and Vascular Remodeling: Extracellular Ca2 + Entry for Angiogenesis, Arteriogenesis and Vasculogenesis. Front. Physiol. 2020, 10, 1618. Available online: https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2019.01618 (accessed on 12 June 2024). [CrossRef] [PubMed]
- Vrenken, K.S.; Jalink, K.; van Leeuwen, F.N.; Middelbeek, J. Beyond ion-conduction: Channel-dependent and -independent roles of TRP channels during development and tissue homeostasis. Biochim. Biophys. Acta Mol. Cell Res. 2016, 1863, 436–446. [Google Scholar] [CrossRef]
- Kim, D.Y.; Kim, K.M.; Kim, E.J.; Jang, W.G. Hypothermia-induced RNA-binding motif protein 3 (RBM3) stimulates osteoblast differentiation via the ERK signaling pathway. Biochem. Biophys. Res. Commun. 2018, 498, 459–465. [Google Scholar] [CrossRef]
- Buccoliero, C.; Dicarlo, M.; Pignataro, P.; Gaccione, F.; Colucci, S.; Colaianni, G.; Grano, M. The Novel Role of PGC1α in Bone Metabolism. Int. J. Mol. Sci. 2021, 22, 4670. [Google Scholar] [CrossRef]
- Shi, H.; Yao, R.; Lian, S.; Liu, P.; Liu, Y.; Yang, Y.Y.; Yang, H.; Li, S. Regulating glycolysis, the TLR4 signal pathway and expression of RBM3 in mouse liver in response to acute cold exposure. Stress 2019, 22, 366–376. [Google Scholar] [CrossRef]
- Hang, K.; Ye, C.; Chen, E.; Zhang, W.; Xue, D.; Pan, Z. Role of the heat shock protein family in bone metabolism. Cell Stress Chaperones 2018, 23, 1153–1164. [Google Scholar] [CrossRef]
- McGee-Lawrence, M.E.; Carpio, L.R.; Bradley, E.W.; Dudakovic, A.; Lian, J.B.; van Wijnen, A.J.; Kakar, S.; Hsu, W.; Westendorf, J.J. Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice. Bone 2014, 66, 277–286. [Google Scholar] [CrossRef]
- Einhorn, T.A.; Gundberg, C.M.; Devlin, V.J.; Warman, J. Fracture healing and osteocalcin metabolism in vitamin K deficiency. Clin. Orthop. Relat. Res. 1988, 237, 219–225. [Google Scholar] [CrossRef]
- Nie, Y.; Yan, Z.; Yan, W.; Xia, Q.; Zhang, Y. Cold exposure stimulates lipid metabolism, induces inflammatory response in the adipose tissue of mice and promotes the osteogenic differentiation of BMMSCs via the p38 MAPK pathway in vitro. Int. J. Clin. Exp. Pathol. 2015, 8, 10875–10886. [Google Scholar]
- Cheng, Z.; Li, A.; Tu, C.L.; Maria, C.S.; Szeto, N.; Herberger, A.; Chen, T.H.; Song, F.; Wang, J.; Liu, X.; et al. Calcium-Sensing Receptors in Chondrocytes and Osteoblasts Are Required for Callus Maturation and Fracture Healing in Mice. J. Bone Min. Res. 2020, 35, 143–154. [Google Scholar] [CrossRef]
- Larson, C.; Opichka, M.; McGlynn, M.L.; Collins, C.W.; Slivka, D. Exercise- and Cold-Induced Human PGC-1α mRNA Isoform Specific Responses. Int. J. Environ. Res. Public Health 2020, 17, 5740. [Google Scholar] [CrossRef]
- Zhang, Z.; Yang, D.; Xiang, J.; Zhou, J.; Cao, H.; Che, Q.; Bai, Y.; Guo, J.; Su, Z. Non-shivering Thermogenesis Signalling Regulation and Potential Therapeutic Applications of Brown Adipose Tissue. Int. J. Biol. Sci. 2021, 17, 2853–2870. [Google Scholar] [CrossRef]
- Wang, H.; Wang, J. Estrogen-related receptor alpha interacts cooperatively with peroxisome proliferator-activated receptor-gamma coactivator-1alpha to regulate osteocalcin gene expression. Cell Biol. Int. 2013, 37, 1259–1265. [Google Scholar] [CrossRef]
- McKee, M.D.; Pedraza, C.E.; Kaartinen, M.T. Osteopontin and wound healing in bone. Cells Tissues Organs 2011, 194, 313–319. [Google Scholar] [CrossRef]
- Boonrungsiman, S.; Gentleman, E.; Carzaniga, R.; Evans, N.D.; McComb, D.W.; Porter, A.E.; Stevens, M.M. The role of intracellular calcium phosphate in osteoblast-mediated bone apatite formation. Proc. Natl. Acad. Sci. USA 2012, 109, 14170–14175. [Google Scholar] [CrossRef]
- Abe, Y.; Fujiwara, Y.; Takahashi, H.; Matsumura, Y.; Sawada, T.; Jiang, S.; Nakaki, R.; Uchida, A.; Nagao, N.; Naito, M.; et al. Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch. Nat. Commun. 2018, 9, 1566. [Google Scholar] [CrossRef] [PubMed]
- Casali, C.; Galgano, L.; Zannino, L.; Siciliani, S.; Cavallo, M.; Mazzini, G.; Biggiogera, M. Impact of heat and cold shock on epigenetics and chromatin structure. Eur. J. Cell Biol. 2024, 103, 151373. [Google Scholar] [CrossRef] [PubMed]
- Li, J.Y.; Wang, T.T.; Ma, L.; Zhang, Y.; Zhu, D. Silencing of Jumonji domain-containing 1C inhibits the osteogenic differentiation of bone marrow mesenchymal stem cells via nuclear factor-κB signaling. World J. Stem Cells 2024, 16, 151–162. [Google Scholar] [CrossRef]
- Zeng, Z.L.; Xie, H. Mesenchymal stem cell-derived extracellular vesicles: A possible therapeutic strategy for orthopaedic diseases: A narrative review. Biomater. Transl. 2022, 3, 175–187. [Google Scholar]
- Wang, Q. Biomaterials Translational—The New Vehicle for Translational Medicine. Biomater. Transl. 2020, 1, 1–2. [Google Scholar] [PubMed]
- Zhang, C.; Cai, D.; Liao, P.; Su, J.W.; Deng, H.; Vardhanabhuti, B.; Ulery, B.D.; Chen, S.Y.; Lin, J. 4D Printing of shape-memory polymeric scaffolds for adaptive biomedical implantation. Acta Biomater. 2021, 122, 101–110. [Google Scholar] [CrossRef]
- El-Husseiny, H.M.; Mady, E.A.; Hamabe, L.; Abugomaa, A.; Shimada, K.; Yoshida, T.; Tanaka, T.; Yokoi, A.; Elbadawy, M.; Tanaka, R. Smart/stimuli-responsive hydrogels: Cutting-edge platforms for tissue engineering and other biomedical applications. Mater. Today Bio 2022, 13, 100186. [Google Scholar] [CrossRef]
- Cheng, Y.; Yu, Y.; Zhang, Y.; Zhao, G.; Zhao, Y. Cold-Responsive Nanocapsules Enable the Sole-Cryoprotectant-Trehalose Cryopreservation of β Cell-Laden Hydrogels for Diabetes Treatment. Small 2019, 15, e19042902. [Google Scholar]
- Molkenova, A.; Choi, H.E.; Lee, G.; Baek, H.; Kwon, M.; Lee, S.B.; Park, J.M.; Kim, J.H.; Han, D.W.; Park, J.; et al. Cold-Responsive Hyaluronated Upconversion Nanoplatform for Transdermal Cryo-Photodynamic Cancer Therapy. Adv. Sci. 2024, 11, 2306684. [Google Scholar] [CrossRef] [PubMed]
- Kleiter, M.M.; Thrall, D.E.; Malarkey, D.E.; Ji, X.; Lee, D.Y.W.; Chou, S.C.; Raleigh, J.A. A comparison of oral and intravenous pimonidazole in canine tumors using intravenous CCI-103F as a control hypoxia marker. Int. J. Radiat. Oncol. Biol. Phys. 2006, 64, 592–602. [Google Scholar] [CrossRef] [PubMed]
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Zakaria, M.; Matta, J.; Honjol, Y.; Schupbach, D.; Mwale, F.; Harvey, E.; Merle, G. Decoding Cold Therapy Mechanisms of Enhanced Bone Repair through Sensory Receptors and Molecular Pathways. Biomedicines 2024, 12, 2045. https://doi.org/10.3390/biomedicines12092045
Zakaria M, Matta J, Honjol Y, Schupbach D, Mwale F, Harvey E, Merle G. Decoding Cold Therapy Mechanisms of Enhanced Bone Repair through Sensory Receptors and Molecular Pathways. Biomedicines. 2024; 12(9):2045. https://doi.org/10.3390/biomedicines12092045
Chicago/Turabian StyleZakaria, Matthew, Justin Matta, Yazan Honjol, Drew Schupbach, Fackson Mwale, Edward Harvey, and Geraldine Merle. 2024. "Decoding Cold Therapy Mechanisms of Enhanced Bone Repair through Sensory Receptors and Molecular Pathways" Biomedicines 12, no. 9: 2045. https://doi.org/10.3390/biomedicines12092045
APA StyleZakaria, M., Matta, J., Honjol, Y., Schupbach, D., Mwale, F., Harvey, E., & Merle, G. (2024). Decoding Cold Therapy Mechanisms of Enhanced Bone Repair through Sensory Receptors and Molecular Pathways. Biomedicines, 12(9), 2045. https://doi.org/10.3390/biomedicines12092045