Thermal Dose and Thermobiophysical Regulation of Skeletal Tissues: A Context-Dependent Framework from Molecular...

Temperature is a biologically active physical variable in skeletal tissues, but apparently contradictory findings often arise because thermal magnitude is reported without the accompanying time, spatial, mechanical, and pathological context. This critical review synthesizes evidence on temperature-dependent regulation of bone and cartilage using a thermal-dose framework that distinguishes local mild hypothermia, chronic systemic cold exposure, adaptive mild heating, and hyperthermic injury. Representative studies indicate that no universal boundary temperature exists: transient exposures of approximately 39-41 °C can support heat-shock-protein-dependent osteogenic or chondrogenic adaptation, whereas longer exposures at the same or slightly higher temperatures may inhibit proliferation; cartilage injury increases steeply around 50-55 °C, while sustained culture at 34-35.5 °C suppresses osteoblast differentiation and promotes osteoclastogenesis. We therefore interpret biological outcome as a function of temperature-time history, spatial gradients, delivery modality, tissue depth, mechanical/osmotic co-stimulation, and disease state rather than nominal temperature alone. At the molecular level, mild heat can be buffered by proteostasis networks and polymodal TRPV4-Ca2+ signaling, whereas excessive thermal load increases protein unfolding/aggregation, oxidative and mitochondrial stress, and remodeling signals from osteocytes and other microenvironmental cells. Evidence is strongest for cell- and tissue-specific response windows, but clinical dose-response relationships remain incompletely validated. We propose a testable multiscale framework that links bioheat transfer, molecular damage-versus-adaptation, and multicellular remodeling, together with a minimum reporting set for thermal interventions. NIR photothermal and magnetothermal biomaterials illustrate the promise of spatially controlled heating, but their translation requires direct target-tissue thermometry, modality-specific dosimetry, and patient-stratified validation.