1. The introduction section is too long and some parts should be moved to the discussion section
2. Line 31, introduction. The authors cite a very low quality paper (Inhibition of GSK-3β Alleviates Collagen II-Induced Rheumatoid Arthritis in Rats) with questionable results, e.g. completely unrealistic cytokine levels.
3. Fig. 1C. The final body weight of CIA animals is significantly higher than in controls.How is this possible? Several studies in mice and rabbits have shown that CIA induces cachexia and animals with active CIA have lower weights (e.g. Cachexia Sarcopenia Muscle. 2018 Jun;9(3):603-612).
4. In this recent paper (Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation, Ann Rheum Dis. 2018 Jul; 77(7): 1053–1062.), the authors show that inactivated GSK3b is a major hallmark of pro-inflammatory macrophages. This contradicts the findings presented here which show the opposite. Please comment.
5. Fig. 2. I can’t see much difference (except in 1D where there are fewer cells) in these pictures. If there is a quantitative difference (e.g. by counting lymphocyte inflitrates on a certain area), the authors should show this in an extra bar chart or box plot.
6. Fig. 4B . Labelling is incorrect. Also whole blots should be supplied in supplementary materials. TNF and IL-6 blot quantification are identical. Please correct. In addition, western blots usually give much higher standard deviations. I would most certainly expect this here, since cytokines are usually determined by ELISA and when done by WB, only intracellular cytokines will be detected. It could well be, that the total amount (secreted + intracellular) is unchanged. Please comment.
7. Language editing is required

Comments:
• For my taste, the title is too long and hard to comprehend; if you want readers to be interested in this study, a more concise title would be more appropriate
• P41 Line 6: a crosstalk is usually between pathways but not between a disease and the ER, please change
• Line 12: …“ TDZD-8, the inhibitor of the glycogen synthase kinase-3β (GSK3β) involved in RA pathogenesis“, an inhibitor is not involved in RA, change
• Line 28: RA induced CD45. Not true. Please change. CD45 is a common leukocyte marker
• Please don’t use the phrase RA for rats, RA is a human disease
• Introduction: p42 line 9: …“ mostly women 1(Ref), which cause inflammation …“ women do not cause inflammation, change
• P42 Line 27: self-eating, please omit, colloquial
• P46 line 41:…“ by inhibiting CIA-induced damaged paws“ paws cannot be inhibited, change
• P46 line 42: …“inhibited arthritis score… score cannot be inhibited, change
• P44 line 12: …“ negative or weak CD45 positive immunostained cells“ that would imply that leukocytes express lower CD45 levels in controls. This is not true. A reduced CD45 staining intensity shows that there are fewer cells. The cellular level of CD45 is the same in arthritic and non-arthritic animals
• P45: 2.5. This sentence is too long and hard to understand
• In general, language is still an issue. The rare a few wrong prepositions, some logical errors and misisng words
• In the methods section, IL-6 and TNF antibodies are mentioned but data is not shown
• I raised this point already but was this was ignored by the authors:
In this recent paper (Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation, Ann Rheum Dis. 2018 Jul; 77(7): 1053–1062.), the authors show that inactivated GSK3b is a major hallmark of pro-inflammatory macrophages. This contradicts the findings presented here which show the opposite. Please comment.

• Discussion is too short and half of it recapitulates results
• Fig. 5: This is no real correlation. It clearly only shows the difference between arthritic and non-arthritic animals. If all animals are included the values on the x axis should be the same for all RF and ACPAs. The dots representing ACPAs and RF are different in each panel. Why is that?
• Fig. 2: CD45 expression is not inhibited. TDZD might decrease leukocyte inflitrates and this can be seen by reduced CD45 staining intensity. Also CD45 is shedded which might explain higher staining intensity in CIA. Please comment.

• Page 3 line 8: grammar issue
• Page 3, line 15: arthritis autoantibodies? Change. Autoantibodies are not against arthritis.
• Page 3, line 46…RA develops from a complex interaction between a variety of innate and adaptive immune cells that ultimately leads to the growth and hyperproliferation of fibroblast-like synoviocytes (FLS).“ FLS do not hyperproliferate due to interaction of innate and adaptive immune cells; rather enhanced cytokine production or interactions between fibroblasts and immune cells induce proliferation.
• Page 10, line 28: However, the level of these parameters in the CIA+TDZD-8 group was significantly elevated compared with the control group of rats (Figure 1B and 1C), which means a partial inhibition was seen. This is misleading; of course there is no complete remission with treatment. Arthritis is already established, meaning autoantibodies are already present at the beginning of treatment, which started at day 21. Also, an intervention after immunization will never completely block arthritis development, not even glucocorticoids.
• Page 11, line 36: …TDZD-8, but still significant to the control group“. Word is missing: elevated?
• Pag 12, line 6: please change the term arthritis autoantibodies to something like... autoantibodies generated during the course of arthritis.
• Discussion is too short