Temperature, heat shock proteins and growth regulation of the bone tissue

  • V. V. Kuibida Hryhorii Skovoroda University in Pereiaslav
  • P. P. Kohanets Hryhorii Skovoroda University in Pereiaslav
  • V. V. Lopatynska Hryhorii Skovoroda University in Pereiaslav
Keywords: thermal zones; osteogenesis mechanism; adenylyl cyclase; protein kinase; Allen’s rule.


Ambient heat modulates the elongation of bones in mammals, and the mechanism of such a plasticity has not been studied completely. The influence of heat on growth and development of bone depends on its values. Five zones of temperature influence on the bone tissue with different biological effects have been distinguished : a) under-threshold thermal zone < 36.6 ºС, insufficient amount of heat is a limiting factor for osteogenesis; b) normal temperature zone 36.6‒37.5 ºС, the processes of breakdown and development of bone in this temperature range is balanced; b) zone of mild thermal shock 39‒41 ºС, the processes of functioning of osteoblasts, osteocytes and formation of the bone tissue intensify; d) the zone of sublethal thermal shock > 42 ºС, growth of bone slows; e) zone of non-critical shock > 50 ºС, bone tissue cells die. We propose a model of the mechanism of influence of heat shock on bone growth. Mild heat shock is a type of stress to which membrane enzymes adenylyl cyclase and cAMP-protein kinase react. Protein kinase A phosphorylates the gene factors of thermal shock proteins, stress proteins and enzymes of energy-generating processes – glycolysis and lipolysis. Heat shock protein HSP70 activates alkaline phosphatase and promotes the process of mineralization of the bone tissue. In the cells, there is intensification in syntheses of insulin-like growth factor-I, factors of mitogenic action, signals of intensification of blood circulation (NO) and synthesis of somatotropin. The affinity between insulin-like growth factor I and its acid-labile subunit decreases, leading to increased free and active insulin-like growth factor I. Against the background of acceleration of the capillarization process, energy generation and the level of stimulators of growth of bone tissue, mitotic and functional activities of producer cells of the bone – osteoblasts and osteocytes – activate. The generally known Allen’s rule has been developed and expanded: “Warm-blooded animals of different species have longer distal body parts (tails) if after birth the young have developed in the conditions of higher temperature”. The indicated tendency is realized through increased biosynthesis of heat shock proteins and other stimulators of growth processes in the bone tissue.


Abreu-Vieira, G., Xiao, C., Gavrilova, O., & Reitman, M. L. (2015). Integration of body temperature into the analysis of energy expenditure in the mouse. Molecular Metabolism, 4(6), 461‒470.

Al-Hilli, F., & Wright, E. A. (1983a). The effects of changes in the environmental temperature on the growth of tail bones in the mouse. International Journal of Experimental Pathology, 64(1), 34‒42.

Al-Hilli, F., & Wright, E. A. (1983b). The short term effects of a supra-lethal dose of irradiation and changes in the environmental temperature on the growth of tail bones of the mouse. International Journal of Experimental Pathology, 64(6), 684‒692.

Allen, J. A. (1877). The Influence of Physical Conditions in the Genesis of Species. Pp. 108‒140.

Al-Zghoul, M. B. (2018). Thermal manipulation during broiler chicken embryogenesis increases basal mRNA levels and alters production dynamics of heat shock proteins 70 and 60 and heat shock factors 3 and 4 during thermal stress. Poultry Science, 97(10), 3661‒3670.

Al-Zghoul, M. B., & El-Bahr, S. M. (2019). Basal and dynamics mRNA expression of muscular HSP108, HSP90, HSF-1 and HSF-2 in thermally manipulated broilers during embryogenesis. BMC Veterinary Research, 15(1), 83.

Al-Zghoul, M., Al-Natour, M., Dalab, A., Alturki, O., Althnaian, T., Al-ramadan, S., Hannon, K., & El-Bahr, S. (2016). Thermal manipulation mid-term broiler chicken embryogenesis: Effect on muscle growth factors and muscle marker genes. Brazilian Journal of Poultry Science, 18, 607–618.

Archer, A. E., Von Schulze, A. T., & Geiger, P. C. (2018). Exercise, heat shock proteins and insulin resistance. Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences, 373, 1738.

Beresford, J. N., Graves, S. E., & Smoothy, C. A. (1993). Formation of mineralized nodules by bone derived cells in vitro: A model of bone formation? American Journal of Medical Genetics, 45(2), 163‒178.

Brunt, V. E., Howard, M. J., Francisco, M. A., Ely, B. R., & Minson, C. T. (2016). Passive heat therapy improves endothelial function, arterial stiffness and blood pressure in sedentary humans. The Journal of Physiology, 594(18), 5329‒5342.

Cazzato, R. L., de Rubeis, G., de Marini, P., Dalili, D., Koch, G., Auloge, P., Garnon, J., & Gangi, A. (2021). Percutaneous microwave ablation of bone tumors: A systematic review. European Radiology, 31, 3530–3541.

Chen, E., Xue, D., Zhang, W., Lin, F., & Pan, Z. (2015). Extracellular heat shock protein 70 promotes osteogenesis of human mesenchymal stem cells through activation of the ERK signaling pathway. Federation of European Biochemical Societies letters, 589, 4088–4096.

Chevalier, C., Kieser, S., Çolakoğlu, M., Hadadi, N., Brun, J., Rigo, D., Suárez-Zamorano, N., Spiljar, M., Fabbiano, S., Busse, B., Ivanišević, J., Macpherson, A., Bonnet, N., & Trajkovski, M. (2020). Warmth prevents bone loss through the gut microbiota. Cell Metabolism, 32(4), 575‒590.

Davenport, J., Jones, T. T., Work, T. M., & Balazs, G. H. (2015). Topsy-turvy: Turning the counter-current heat exchange of leatherback turtles upside down. Biology Letters, 11(10), 0592.

Dawson, N. J., & Keber, A. W. (1979). Physiology of heat loss from an extremity: The tail of the rat. Clinical and Experimental Pharmacology and Physiology, 6(1), 69‒80.

De Tommasi, F., Massaroni, C., Grasso, R. F., Carassiti, M., & Schena, E. (2021). Temperature monitoring in hyperthermia treatments of bone tumors: State-of-the-art and future challenges. Sensors, 21(16), 5470.

Demidov, S. V., Kostromin, A. N., Kuibeda, V. V., Chernaia, I. V., & Borovok, M. I. (1991). Effect of thymagen, thymalin and vilosen on the cAMP and cGMP levels and phosphodiesterase activity in spleen lymphocytes during sensitization and anaphylactic shock. The Ukrainian Biochemical Journal, 63, 104‒106.

Drobot, L. B., Samoylenko, A. A., Vorotnikov, A. V., Tyurin-Kuzmin, P. A., Bazalii, A. V., Kietzmann, T., Tkachuk, V. A., & Komisarenko, S. V. (2013). Reactive oxygen species in signal transduction. The Ukrainian Biochemical Journal, 85, 209‒217.

Du, J., He, Z., Cui, J., Li, H., Xu, M., Zhang, S., Zhang, S., Yan, M., Qu, X., & Yu, Z. (2021). Osteocyte apoptosis contributes to cold exposure-induced bone loss. Frontiers in Bioengineering and Biotechnology, 733582.

Erdsack, N., McCully Phillips, S. R., Rommel, S. A., Pabst, D. A., McLellan, W. A., & Reynolds, J. E. (2018). Heat flux in manatees: An individual matter and a novel approach to assess and monitor the thermal state of Florida manatees (Trichechus manatus latirostris). Journal of Comparative Physiology B, 188(4), 717–727.

Falfushynska, H. I., Horyn, O. I., Poznansky, D. V., Osadchuk, D. V., Savchyn, T. О., Krytskyi, T. І., Merva, L. S., & Hrabra, S. Z. (2019). Oxidative stress and thiols depletion impair tibia fracture healing in young men with type 2 diabetes. The Ukrainian Biochemical Journal, 91(6), 67‒78.

Goldberg, S. N., Gazelle, G. S., & Mueller, P. R. (2000). Thermal ablation therapy for focal malignancy. American Journal of Roentgenology, 174, 323–331.

Gordon, C. J., Aydin, C., Repasky, E. A., Kokolus, K. M., Dheyongera, G., & Johnstone, A. F. (2014). Behaviorally mediated, warm adaptation: A physiological strategy when mice behaviorally thermoregulate. Journal of Thermal Biology, 44, 41‒46.

Hafen, P. S., Preece, C. N., Sorensen, J. R., Hancock, C. R., & Hyldahl, R. D. (2018). Repeated exposure to heat stress induces mitochondrial adaptation in human skeletal muscle. Journal of Applied Physiology, 125(5), 1447‒1455.

Hang, K., Ye, C., Chen, E., Zhang, W., Xue, D., & Pan, Z. (2018). Role of the heat shock protein family in bone metabolism. Cell Stress and Chaperones, 23, 1153–1164.

Hankenson, F. C., Marx, J. O., Gordon, C. J., & David, J. M. (2018). Effects of Rodent thermoregulation on animal models in the research environment. Comparative Medicine, 68(6), 425‒438.

Hasenour, C. M., Berglund, E. D., & Wasserman, D. H. (2013). Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver. Molecular and Cellular Endocrinology, 366(2), 152‒162.

Herzig, S., & Shaw, R. J. (2018). AMPK: Guardian of metabolism and mitochondrial homeostasis. Nature Reviews Molecular Cell Biology, 19(2), 121‒135.

Heyning, J. E. (2001). Thermoregulation in feeding baleen whales: Morphological and physiological evidence. Aquatic Mammals, 27(3), 284–288.

Holman, S. R., & Baxter, R. C. (1996). Insulin-like growth factor binding protein-3: Factors affecting binary and ternary complex formation. Growth Regulation, 6(1), 42‒47.

Kostromin, A. P., Berdyshev, G. D., Demidov, S. V., & Kuibeda, V. V. (1984). Age-associated changes in content of cyclic adenosine-3', 5'-monophosphate (cAMP), cyclic guanosine-3',5'-monophosphate (cGMP) and in activity of phosphodiesterase-cAM (pDE-cAM) in spleen T-lymphocytes from C3HA mice. Zeitschrift für Alternsforschung, 39(6), 351‒355.

Kostromin, A. P., Kuibeda, V. V., Boiko, N. A., Demidov, S. V., & Berdyshev, G. D. (1986). cAMP and cGMP (EVE) changes in immune competent cells under sensibilization and anaphylactic shock of animals of different age. Zeitschrift für Alternsforschung, 41(1), 3‒7.

Kuibida, V., Kokhanets, P., & Lopatynska, V. (2021). Mechanism of strengthening the skeleton using plyometrics. Journal of Physical Education and Sport, 21(3), 1309‒1316.

Laukkanen, J. A., Laukkanen, T., & Kunutsor, S. K. (2018). Cardiovascular and other health benefits of sauna bathing: A review of the evidence. Mayo Clinic Proceedings, 93(8), 1111‒1121.

Lee, S. C., Hsiao, J. K., Yang, Y. C., Haung, J. C., Tien, L. Y., Li, D. E., & Tsai, S. M. (2021). Insulin-like growth factor-1 positively associated with bone formation markers and creatine kinase in adults with general physical activity. Journal of Clinical Laboratory Analysis, 35(8), e23799.

Leicht, C. A., James, L. J., Briscoe, J. H. B., & Hoekstra, S. P. (2019). Hot water immersion acutely increases postprandial glucose concentrations. Physiological Reports, 7(20), e14223.

Leon, S. A., Asbell, S. O., Arastu, H. H., Edelstein, G., Packel, A. J., Sheehan, S., Daskal, I., Guttmann, G. G., & Santos, I. (1993). Effects of hyperthermia on bone. II. Heating of bone in vivo and stimulation of bone growth. International Journal of Hyperthermia, 9(1), 77–87.

Li, M., Fuchs, S., Böse, T., Schmidt, H., Hofmann, A., Tonak, M., Unger, R., & Kirkpatrick, C. J. (2014). Mild heat stress enhances angiogenesis in a co-culture system consisting of primary human osteoblasts and outgrowth endothelial cells. Tissue engineering, Part C, Methods, 20(4), 328‒339.

Lui, J. C., Nilsson, O., & Baron, J. (2014). Recent research on the growth plate: Recent insights into the regulation of the growth plate. Journal of Molecular Endocrinology, 53(1), 22.

Migulin, O. (1938). Mammals of the UkrSSR (Data of the fauna). UkrSSR Academy of Science, Kiev (in Ukrainian).

Morris, C. C., Myers, R., & Field, S. B. (1977). The response of the rat tail to hyperthermia. The British Journal of Radiology, 50(596), 576‒580.

Moynagh, M. R., Kurup, A. N., & Callstrom, M. R. (2018). Thermal ablation of bone metastases. Seminars in Interventional Radiology, 35(4), 299‒308.

Ogawa, H. (1990). Effects of the localized thermal enhancement on new bone formation following mechanical expansion of the rat sagittal suture. The Journal of Japan Orthodontic Society, 49(6), 485‒496.

Oliveira Silva, M., Gregory, J. L., Ansari, N., & Stok, K. S. (2020). Molecular signaling interactions and transport at the osteochondral interface. A Frontiers in Cell and Developmental Biology, 8, 750.

Ota, T., Nishida, Y., Ikuta, K., Kato, R., Kozawa, E., Hamada, S., Sakai, T., & Ishiguro, N. (2017). Heat-stimuli-enhanced osteogenesis using clinically available biomaterials. PLoS One, 12, e0181404.

Politis, S. N., Mazurais, D., Servili, A., Zambonino-Infante, J. L., Miest, J. J., Sørensen, S. R., Tomkiewicz, J., & Butts, I. A. E. (2017). Temperature effects on gene expression and morphological development of European eel, Anguilla anguilla larvae. PLoS One, 12(8), e0182726.

Povoroznyuk, V. V., Dedukh, N. V., Bystrytska, M. A., & Shapovalov, V. S. (2021). Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms. Regulatory Mechanisms in Biosystems, 12(2), 212‒227.

Racine, H. L., & Serrat, M. A. (2020). The actions of IGF-1 in the growth plate and its role in postnatal bone elongation. Current Osteoporosis Reports, 18(3), 210–227.

Racine, H. L., Meadows, C. A., Ion, G., & Serrat, M. A. (2018). Heat-induced limb length asymmetry has functional impact on weight bearing in mouse hindlimbs. Frontiers in Endocrinology, 9, 289.

Rakhmetov, A. D., Lee, S. P., Ostapchenko, L. I., & Chae, H. Z. (2016). Prx II and CKBB proteins interaction under physiologic al and thermal stress conditions in A549 and HeLa cells. The Ukrainian Biochemical Journal, 88(1), 61‒68.

Reichholf, J. (2002). Mlekopitajushchie [Mammals]. Astrel, Moscow (in Russian).

Robbins, A., Tom, C. A. T. M. B., Cosman, M. N., Moursi, C., Shipp, L., Spencer, T. M., Brash, T., & Devlin, M. J. (2018). Low temperature decreases bone mass in mice: Implications for humans. American Journal of Biological Anthropology, 167(3), 557‒568.

Rommel, S. A., & Caplan, H. (2003). Vascular adaptations for heat conservation in the tail of Florida manatees (Trichechus manatus latirostris). Journal of Anatomy, 202(4), 343‒353.

Schipper, L., van Heijningen, S., Karapetsas, G., van der Beek, E. M., & van Dijk, G. (2020). Individual housing of male C57BL/6J mice after weaning impairs growth and predisposes for obesity. PLoS One, 15(5), e0225488.

Serrat, M. A., Efaw, M. L., & Williams, R. M. (2014). Hindlimb heating increases vascular access of large molecules to murine tibial growth plates measured by in vivo multiphoton imaging. Journal of Applied Physiology, 116(4), 425‒438.

Serrat, M. A., Schlierf, T. J., Efaw, M. L., Shuler, F. D., Godby, J., Stanko, L. M., & Tamski, H. L. (2015). Unilateral heat accelerates bone elongation and lengthens extremities of growing mice. Journal of Orthopaedic Research, 33(5), 692–698.

Serrat, M. A., Williams, R. M., & Farnum, C. E. (2010). Exercise mitigates the stunting effect of cold temperature on limb elongation in mice by increasing solute delivery to the growth plate. Journal of Applied Physiology, 109(6), 1869‒1879.

Shui, C., & Scutt, A. (2001). Mild heat shock induces proliferation, alkaline phosphatase activity, and mineralization in human bone marrow stromal cells and Mg-63 cells in vitro. Journal of Bone and Mineral Research, 16(4), 731‒741.

Škop, V., Guo, J., Liu, N., Xiao, C., Hall, K. D., Gavrilova, O., & Reitman, M. L. (2020a). Mouse thermoregulation: Introducing the concept of the thermoneutral point. Cell Reports, 31(2), 107501.

Škop, V., Liu, N., Guo, J., Gavrilova, O., & Reitman, M. L. (2020b). The contribution of the mouse tail to thermoregulation is modest. American Journal of Physiology, Endocrinology and Metabolism, 319(2), E438–E446.

Smolka, M. B., Zoppi, C. C., Alves, A. A., Silveira, L. R., Marangoni, S., Pereira-Da-Silva, L., Novello, J. C., & Macedo, D. V. (2000). HSP72 as a complementary protection against oxidative stress induced by exercise in the soleus muscle of rats. American Journal of Physiology, Regulatory, Integrative and Comparative Physiology, 279(5), R1539.

Starling, S. (2020). Warmth prevents bone loss. Nature Reviews, Endocrinology, 16(12), 679.

Stevens, P. M. (2016). The role of guided growth as it relates to limb lengthening. Journal of Children’s Orthopaedics, 10(6), 479‒486.

Stryjek, R., Parsons, M. H., & Bebas, P. (2021). A newly discovered behavior ('tail-belting') among wild rodents in sub zero conditions. Scientific Reports, 11(1), 22449.

Tan, C. L., & Knight, Z. A. (2018). Regulation of body temperature by the nervous system. Neuron, 98(1), 31‒48.

Tomasian, A., & Jennings, J. W. (2020). Percutaneous minimally invasive thermal ablation of osseous metastases: Evidence-based practice guidelines. American Journal of Roentgenology, 215(2), 502‒510.

Toro, V., Siquier-Coll, J., Bartolomé, I., Pérez-Quintero, M., Raimundo, A., Muñoz, D., & Maynar-Mariño, M. (2021). Effects of twelve sessions of high-temperature sauna baths on body composition in healthy young men. International Journal of Environmental Research and Public Health, 18(9), 4458.

Trieb, K., Blahovec, H., & Kubista, B. (2007). Effects of hyperthermia on heat shock protein expression, alkaline phosphatase activity and proliferation in human osteosarcoma cells. Cell Biochemistry and Function, 25(6), 669‒672.

Villarreal, J. A., Schlegel, W. M., & Prange, H. D. (2007). Thermal environment affects morphological and behavioral development of Rattus norvegicus. Physiology and Behavior, 91(1), 26‒35.

Wang, L., Shao, Y. Y., & Ballock, R. T. (2010). Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of beta-catenin signaling. Journal of Bone and Mineral Research, 25(5), 1138‒1146.

Young, A. A., & Dawson, N. J. (1982). Evidence for on-off control of heat dissipation from the tail of the rat. Canadian Journal of Physiology and Pharmacology, 60(3), 392‒398.

Zhang, P., Hamamura, K., Turner, C. H., & Yokota, H. (2010). Lengthening of mouse hindlimbs with joint loading. Journal of Bone and Mineral Metabolism, 28(3), 268‒275.

How to Cite
Kuibida, V. V., Kohanets, P. P., & Lopatynska, V. V. (2022). Temperature, heat shock proteins and growth regulation of the bone tissue . Regulatory Mechanisms in Biosystems, 13(1), 38-45. https://doi.org/10.15421/022205