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  1. Evaluation Summary:

    This is the study to determine the effects of mechanical loading on temperature changes in the joint and how the mechano-thermal transduction may influence chondrocyte behavior. This manuscript will be of interest to the clinicians and researchers who are working on tissue engineering and cartilage regeneration. The study has high clinical relevance. It provides new evidence that the mechanical stimuli plus with the temperature increase could influence the cell chondrogenic response. The data support the conclusions of the manuscript within the current context, although several issues need to be addressed.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

  2. Reviewer #1 (Public Review):

    Nasrollahzadeh et al. tried to explore the optimal physiological culture conditions, like the thermo and the mechanical environments for chondrocytes in vitro . For this purpose, an extracorporeal model system is designed to simulating the joint movement generated mechanical stimulation and self-heating. As the authors explained, this model system consists of 2 parts: 1). a fatigue resistant hydrogel functionalized by RGD peptides and loaded with human chondro-progenitor cells to recapitulate cartilage viscoelastic properties; 2). a modular bioreactor to independently control applied mechanical loading, temperature increase as well as gas concentration and humidity levels during stimulation. Whereafter, the individual and cooperative effects of temperature and mechanical loading are investigated based on this system, and chondrogenic related gene expressions, like Col2a, Agc et al. are employed to determine the cartilage regeneration. The results indicated that the loading induced self-heating significantly enhance the chondrogenic responses. Furthermore, the role of Ca2+ signaling in thermo-mechanotransduction process is studied. The TRPV4 ion channels are chosen as model and the involvement is confirmed by the with or without of TRPV4 agonists and inhibitors. In general, the conclusions of this paper are mostly well supported by data, but some aspects of image acquisition and data analysis need to be clarified and extended.

    1. The authors functionalized the hydrogel with RGD-peptide to improve the cell adhesion and spreading on the scaffold, so hydroxylation and RGD grafting protocols are performed. Whether these reactions change the surface morphology and further influence the cell morphology ? If more details about the surface morphology, such as SEM images can be provided, it will be enlightening.

    2. Although gene expression is one of the direct evidences for inducing chondroblast differentiation, more detection methods, such as GAG expression can be provided to make it more convincing.

    3. As the authors hypothesize, calcium signaling is a major mechanism of action in transduction of thermo-mechanical cues sensed by TRPV4 channels. However, the available data on calcium signaling pathways do not support this conclusion strongly.

    4. It's better to numbering the Figures in SI section according to the sequence in which they appeared in the manuscript.

  3. Reviewer #2 (Public Review):

    This is an interesting and exciting study that addresses a topic in cartilage mechanobiology that has generally been neglected, that is, the effects of mechanical loading on temperature changes in the joint, and how that might affect cell response to loading. I think the work is a major breakthrough. There are some specific questions about the model system that could use further explanation or discussion to improve the impact of the work.