Effects of Thermal Environment on Bone Microenvironment: A Narrative Review
Abstract
1. Introduction
2. Effects of Thermal Environment on Macroscopic Structure of Bones
2.1. Effects of Thermal Environment on Bone Morphology
2.2. Effects of Thermal Environment on Bone Biomechanics
2.3. Effects of Thermal Environment on Bone Mass
2.4. Effects of Thermal Environment on Bone Metabolism
3. Effects of Thermal Environment on Bone Cells
3.1. Effects of Thermal Environment on BMSCs
3.2. Effects of Thermal Environment on Osteoblasts
3.3. Effects of Thermal Environment on Osteocytes
3.4. Effects of Thermal Environment on Osteoclasts
4. Effects of Thermal Environment on Bone Microenvironment
4.1. Effects of Thermal Environment on Bone Nerves
4.2. Effects of Thermal Environment on Bone Angiogenesis
4.3. Effects of Thermal Environment on Bone Marrow Fat
5. Methods
6. Future Perspectives
7. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
activating transcription factor 4 | ATF4 |
alkaline phosphatase | ALP |
angiopoietin-1 | Ang-1 |
angiopoietin-2 | Ang-2 |
apoptotic protease activating factor 1 | Apaf-1 |
bone marrow mesenchymal stem cells | BMSCs |
bone mineral density | BMD |
bone morphogenetic protein-2 | BMP-2 |
brain-derived neurotrophic factor | BDNF |
calcitonin gene-related peptide | CGRP |
cysteine-aspartic protease-3 | caspase-3 |
downregulating cathepsin K | Ctsk |
Heat shock 70-kDa protein 1A | HSPA1A |
heat shock protein 27 | HSP27 |
heat shock protein 70 | HSP70 |
heat shock protein 90 | HSP90 |
heat shock proteins | HSPs |
interleukin-11 | IL-11 |
interleukin-6 | IL-6 |
leptin | LEP |
matrix metalloproteinase 9 | Mmp9 |
nerve growth factor | NGF |
neuropeptide Y | NPY |
norepinephrine | NE |
osteocalcin | Ocn |
osteopontin | Opn |
osteoprotegerin | Opg |
p75 neurotrophin receptor | p75NTR |
parathyroid hormone | PTH |
phosphatase 5b | Trap5b |
precursor of caspase-9 | procaspase-9 |
receptor activator of nuclear factor kappa-B ligand | RANKL |
Runt-related transcription factor 2 | Runx2 |
second mitochondria-derived activator of caspase | Smac |
substance P | SP |
succinic dehydrogenase | SDH |
transforming growth factor-β | TGF-β |
transient receptor potential vanilloid 4 | TRPV4 |
tropomyosin receptor kinase A | TrkA |
tumor necrosis factor α | TNF-α |
vascular endothelial growth factor | VEGF |
vasoactive intestinal peptide | VIP |
X-linked inhibitor of apoptosis protein | XIAP |
β-adrenergic receptors | β-AR |
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Study Design/Method | Species/Cell Type | Temperature | Observable Pros/Cons | Reference |
---|---|---|---|---|
Logistic regression, controlling for age, sex, vaccination status, sanitation, and wealth index | Children | <30 °C 30–35 °C ≥35 °C | Pros: promotes limb growth Cons: may stunt growth | [18] |
Unilateral heat exposure on mice for 14 days; bone growth measured | C57BL/6 mice | 40 °C 30 °C | Pros: increased femur/tibia length Cons: no effect on humerus | [19] |
Daily 40 °C heat treatment on right limb for 40 min over 7 days; X-ray and OTC labeling measured bone length | C57BL/6 mice | 40 °C 30 °C | Pros: measured bone length changes Cons: partial data used | [20] |
16S rRNA, RNA sequencing, and microbiome transplantation | mice | 34 °C | Pros: improved bone strength Cons: warmth affected food intake | [13] |
Studied effects of cold, noise, and heat stress on bone cortical thickness | rats | 10 °C 21.5 °C 33 °C | Cons: heat stress negatively impacted bone thickness | [29] |
Randomized controlled trial with tibial loading and Raloxifene treatment | mice | 22 °C 32 °C | Pros: improved bone structure Cons: thermoneutral caused weight loss | [30] |
Heat exposure on pregnant rats; offspring skeletal malformations evaluated | rats | 37 °C ≥42 °C 41 °C 42 °C | Cons: high temperature caused skeletal malformations | [34] |
Heat shock on pregnant rats; embryos analyzed for protein synthesis | rats | 37–38° 41 °C 42–42.5 °C | Cons: heat caused developmental abnormalities | [35] |
Cell viability and mechanical function tests on heated femurs | rats | 45–60 °C 50 °C to 90 °C | Cons: 60 °C killed bone cells | [39] |
Randomized controlled trial with mice housed at 22 °C or 32 °C | mice | 32 °C | Pros: 32 °C suppressed bone loss Cons: 22 °C caused bone loss | [49] |
6-week sauna study on young men; bone density measured | Humans | 100 ± 2 °C | Pros: increased bone density | [50] |
Heat shock on hMSC-TERT cells; osteogenic differentiation assessed | hBMSC | 41 °C 42.5 °C 44 °C | Pros: enhanced osteogenic differentiation Cons: long-term heat may have negative effects | [53] |
Heat shock on hBMSCs and Mg-63 cells; proliferation and mineralization measured | hBMSC | 33–45 °C | Pros: 39 °C and 41 °C enhanced mineralization Cons: 42.5 °C and 45 °C inhibited proliferation | [54] |
Mild heat stress on osteoblasts and endothelial cells; angiogenesis and osteogenesis assessed | pOB OECs (Osteoblasts) | 41 °C | Pros: enhanced angiogenesis and osteogenesis | [58] |
Study Design/Method | Species/Cell Type | Temperature | Observable Pros/Cons | Reference |
---|---|---|---|---|
Sauna sessions (30 min) 3×/week; blood samples pre/post sauna; qRT-PCR for HSPA1A, HSPB1, IL6, and IL10 mRNA; and ANOVA | Humans | 982 °C, 18 ± 2 °C | Pros: athletes showed better heat stress adaptation (↑IL10, ↓IL6 mRNA) | [66] |
Lentiviral overexpression of HSPA1A in rBMSCs; qPCR, WB, IF for ALP, RUNX2, OCN, and COL1A1; ALP activity, ARS, micro-CT, and histology; DKK1 to validate Wnt/β-catenin; and cell sheet transplantation in rat fracture model | Rats | 37 °C | Pros: HSPA1A overexpression enhanced osteogenic differentiation (↑ALP, RUNX2, OCN, COL1A1, and calcium deposition) via Wnt/β-catenin activation | [67] |
Heat stress (42 °C for 0–60 min) on MSCs; WB, ICC; ANOVA, Newman–Keuls post-hoc analysis | Rats | 42 °C 37 °C | Pros: heat stress significantly induced Hsp27 (48×) and Hsp70 (174×) expression, peaking at 48 h and returning to baseline by 120 h | [68] |
Three lentiviral vectors tested for transduction efficiency in rat and human MSCs; cell passage, cryopreservation, species effects, and hypoxia/ischemia survival with HSP70 overexpression | Rats Humans | 37 °C | Pros: HSP70 overexpression enhanced MSC survival under hypoxia/ischemia | [73] |
HSP at 42 °C for 1 h on BMSCs; CCK-8, FC (Annexin V-FITC/PI), and WB for HSP70/HSP90 | Rodents | 42 °C | Pros: HSP reduced BMSC apoptosis, enhanced proliferation, upregulated HSP70/HSP90, and protected GCs from cisplatin-induced apoptosis | [76] |
Long-term heat exposure (40 °C) on chondrocytes, osteoblasts, MC3T3E1, ROS 17/28; cell counting, FC, Rh123 staining, Coulter counter, and BCA | Rabbits, Mice, Humans | 40 °C | Pros: chondrocytes showed increased proliferation at 40 °C Cons: osteoblasts, MC3T3E1, and ROS 17/28 cells had reduced proliferation and viability at 40 °C | [80] |
Heat shock (33 °C to 45 °C) on hBMSCs and Mg-63; BrdU, crystal violet, ALP assay, and ARS staining | Humans | 33 °C 39 °C 41 °C 425 °C 45 °C | Pros: 39 °C and 41 °C enhanced proliferation, ALP activity, and mineralization Cons: 425 °C and 45 °C inhibited proliferation; 33 °C had no significant effect | [54] |
MC3T3-E1 exposed to 44 °C for 0–8 min; HSPs (HSP27, HSP47, HSP70), bone-related proteins (OPN, OCN, OPG, BSP, ALP, MMP-9), VEGF, and MTS assay | Mice | 44 °C | Pros: heat stress alone or with GFs induced HSPs (especially HSP70), ↑OPG, and ↑VEGF Cons: heat stress inhibited MMP-9, potentially affecting bone remodeling | [81] |
Heat stimulation (37 °C to 50 °C) on MG-63; TOPflash/FOPflash luciferase assay, PCR array for Wnt-related genes, and inhibitors (LY294002, rapamycin, U0126, and Dkk-1) | Humans | 37 °C 448 °C 466 °C 475 °C | Pros: Heat activated Wnt signaling, ↑β-catenin nuclear accumulation, and ↑Wnt ligands (Wnt1, Wnt3a, Wnt8a, and Wnt10a) Cons: high temperatures (eg, 475 °C) may inhibit cells | [85] |
Heat exposure (47 °C for 1 min) on MLO-Y4; fluorescence microscopy, FC, RT-PCR, and co-culture experiments | Mice | 47 °C 37 °C | Pros: heat-treated cells influenced neighboring cells via secreted factors | [91] |
RCT: 90 min cycling at 15 °C (CON) or 35 °C (HEAT); core temp (Trec), muscle temp (Tmus), HR, RPE, and blood samples (cytokines, hormones, metabolites, and WBC count) | Humans | 15 °C 35 °C | Pros: HEAT group showed ↑Trec, ↑Tmus, and ↑stress hormones (adrenaline, noradrenaline) | [97] |
Study Design/Method | Species/Cell Type | Temperature | Observable Pros/Cons | Reference |
---|---|---|---|---|
ELISA for CGRP, tested cannabinoids (anandamide, THC) on CGRP release | Mice (wild-type, CB1−/−, TRPV1−/−) | 47 °C | Pros: TRPV1 activation linked to CGRP release Cons: TRPV1 knockout mice showed reduced heat-induced CGRP release | [101] |
Micro-CT, histology (H&E), IHC, RT-qPCR, ELISA, WB, and BrdU assay | Rats (hBMSCs) | 37 °C | Pros: CGRP inhibited TNF-α, reduced inflammation, regulated bone markers (RANKL, OPG, and OPN) | [102] |
BMSCs isolation, osteogenic induction; FC, IHC, qPCR, WB, and Transwell assay | Rats (hBMSCs) | 37 °C | Pros: SP ↑BMP-2, osteogenic genes (ALP, collagen I, osteocalcin, and RUNX2), VEGF, and migration; activated Wnt/β-catenin | [106] |
BMSCs and BMMs culture; ALP activity, osteocalcin, and RANKL levels; WB, ELISA, TRAP staining, and immunofluorescence | Mice (hBMSCs, BMMs, RAW 2647) | 37 °C | Pros: SP ↑ALP, Runx2, mineralization; ↑TRAP+ cells, bone resorption; and activated NF-κB | [107] |
RT-qPCR for NPY and ASIP mRNA; ANOVA, Bonferroni test | Gallus gallus domesticus | 40 °C 30 °C | Pros: acute heat stress ↑NPY expression | [109] |
Immersion in 41 °C water, cycling in 41 °C environment; rectal temp, heart rate, and RIA for hormone levels | Humans | 41 °C 37 °C 10 °C | Pros: heat load ↑PRL, β-endorphin, and VIP levels | [112] |
Calcium imaging, IHC, WB, ELISA, qPCR, TRPV3 inhibitors, and behavioral analysis | Humans (keratinocytes) Mice (C57BL/6) | 22–23 °C 33 °C 37 °C 39 °C 36–38 °C | Pros: TRPV3 ↑channel activity under heat stress | [114] |
NGF treatment, inhibitors (LY294002, U1026), shRNA TrkA knockdown; migration, tube formation assays, and WB | Humans (chondrocytes HMVEC) | 37 °C | Pros: NGF ↑FGF2 via PI3K/Akt and ERK/MAPK, promoting angiogenesis | [115] |
Immersion in 42 °C or 35 °C water; core temp, MAP, HR, plasma cortisol, BDNF, S100b, and blood cell count; and repeated measures ANOVA | Humans | 42 °C 35 °C | Pros: hot HOI ↑serum BDNF levels | [117] |
Transwell co-culture, MTT assay, ALP staining, Alizarin red staining, ELISA for NGF/BDNF, RT-qPCR, ANOVA, and Newman–Keuls test | Rats (Schwann cells, osteoblasts) | 37 °C | Pros: BDNF and NGF ↑osteoblast proliferation and differentiation | [118] |
Cell culture (MM cells, BMSCs, and pre-OCs), WB, immunofluorescence, ELISA, co-culture, SCID-rab mouse model, and inhibitors (U0126, LY204002) | Humans (hBMSCs pre-OCs), Mice (SCID-rab) | 37 °C | Pros: BDNF ↑RANKL via ERK; BDNF inhibition ↓RANKL, ↓osteoclast activity | [119] |
Immunoprecipitation, WB, chemical crosslinking, cell proliferation, tube formation assays, Apoe−/− mouse model, and siRNA knockdown | Humans (HAECs), Mice (Apoe−/−) | 37 °C | Pros: HSP70 ↑BMP-4 effects, mediated IL-6 pro-calcification | [120] |
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Yin, J.; Guan, Q.; Chen, M.; Cao, Y.; Zou, J.; Zhang, L. Effects of Thermal Environment on Bone Microenvironment: A Narrative Review. Int. J. Mol. Sci. 2025, 26, 3501. https://doi.org/10.3390/ijms26083501
Yin J, Guan Q, Chen M, Cao Y, Zou J, Zhang L. Effects of Thermal Environment on Bone Microenvironment: A Narrative Review. International Journal of Molecular Sciences. 2025; 26(8):3501. https://doi.org/10.3390/ijms26083501
Chicago/Turabian StyleYin, Jiahao, Qiao Guan, Minyou Chen, Yanting Cao, Jun Zou, and Lingli Zhang. 2025. "Effects of Thermal Environment on Bone Microenvironment: A Narrative Review" International Journal of Molecular Sciences 26, no. 8: 3501. https://doi.org/10.3390/ijms26083501
APA StyleYin, J., Guan, Q., Chen, M., Cao, Y., Zou, J., & Zhang, L. (2025). Effects of Thermal Environment on Bone Microenvironment: A Narrative Review. International Journal of Molecular Sciences, 26(8), 3501. https://doi.org/10.3390/ijms26083501