BMB Reports 2022; 55(5): 226-231
Endoplasmin regulates differentiation of tonsil-derived mesenchymal stem cells into chondrocytes through ERK signaling
Hye Ryeong Kim1,# , Hyeongrok Choi1,#, Soon Yong Park2, Young-Chul Song3, Jae-Ho Kim3, Sangin Shim4, Woojin Jun5, Kyung-Jin Kim6, Jin Han7, Seung-Wook Chi8, Sun-Hee Leem9 & Jin Woong Chung1,*
1Department of Biological Science, Dong-A University, Busan 49315, 2Department of Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan 46033, 3Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, 4Department of Agronomy, Gyeongsang National University, Jinju 52828, 5Department of Food and Nutrition, Chonnam National University, Gwangju 61186, 6Department of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, 7Department of Physiology, College of Medicine, Inje University, Busan 47392, 8Disease Target Structure Research Center, KRIBB, Daejeon 34141, 9Department of Health Sciences, Dong-A University, Busan 49315, Korea
Correspondence to: Tel: +82-51-200-7270; Fax: +82-51-200-7269; E-mail:
#These authors contributed equally to this work.
Received: December 3, 2021; Revised: January 6, 2022; Accepted: January 6, 2022; Published online: May 31, 2022.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
It is well-known that some species of lizard have an exceptional ability known as caudal autotomy (voluntary self-amputation of the tail) as an anti-predation mechanism. After amputation occurs, they can regenerate their new tails in a few days. The new tail section is generally shorter than the original one and is composed of cartilage rather than vertebrae bone. In addition, the skin of the regenerated tail distinctly differs from its original appearance. We performed a proteomics analysis for extracts derived from regenerating lizard tail tissues after amputation and found that endoplasmin (ENPL) was the main factor among proteins up-regulated in expression during regeneration. Thus, we performed further experiments to determine whether ENPL could induce chondrogenesis of tonsil-derived mesenchymal stem cells (T-MSCs). In this study, we found that chondrogenic differentiation was associated with an increase of ENPL expression by ER stress. We also found that ENPL was involved in chondrogenic differentiation of T-MSCs by suppressing extracellular signal-regulated kinase (ERK) phosphorylation.
Keywords: Chondrocytes, Differentiation, Endoplasmin, Lizard tail extracts (LTEs), Tonsil-derived mesenchymal stem cells (T-MSCs)

Stem cells are considered as the most effective therapeutic materials in regenerative medicine. Among stem cells, mesenchymal stem cells (MSCs) are easy to acquire and display high proliferation rates with a self-renewal ability (1-3). MSCs are most often used in research on joint-related diseases as they can differentiate into cells of mesodermal lineages (e.g., bone, fat, and cartilage) (4-7). Although MSCs can be obtained from various tissues, we used tonsil-derived mesenchymal stem cells (T-MSCs) in this study. T-MSCs have better proliferation rate and differentiation capabilities than MSCs derived from other tissues (8-10). Once chondrogenic differentiation proceeds, various chondrocyte-specific polysaccharides and proteoglycans, including aggrecan (AGG) and collagen type II (COL2), accumulate to form glycosaminoglycans (GAGs) (11-13).

Some lizard species have an exceptional ability known as caudal autotomy as their anti-predation mechanism. After amputation occurs, these species could regenerate their new tails within a few days (14, 15). However, the new tail is generally shorter than the original one, and it consists of cartilage rather than vertebrae bone. Therefore, we assumed that lizards possess a remarkable capability for chondrogenic differentiation (16, 17).

In this study, we investigated whether extracts derived from regenerating lizard tail tissues could induce chondrogenic differentiation of MSCs. In a previous study involving proteomics analysis, we have identified some factors in extracts derived from a regenerating lizard tail following an amputation (18). Among various factors, endoplasmin (ENPL) attracted our attention. ENPL, which belongs to the chaperone heat shock protein 90 (HSP90) family, is known to affect the folding of specific proteins as well as the survival and proliferation of cells (19-23). Thus, we investigated whether human ENPL could induce chondrogenesis. Consequently we found that ENPL was indeed involved in chondrogenic differentiation of T-MSCs by suppressing ERK phosphorylation. Our findings suggest a novel role of ENPL in chondrogenic differentiation. For the first time, this study demonstrates that ENPL could be a solution to over the limitation of MSC-based cell therapy.


Lizard tail extracts (LTEs) induce the expression of chondrogenic specific cell markers in T-MSCs by regulating ENPL

First, we performed WST-1 assay to determine the cell viability of T-MSCs after treatment with LTEs. It was confirmed that LTEs at concentrations of 0-20 μg/ml did not exert a significant effect on T-MSCs survival (Fig. 1A). The concentration of LTEs to be added to the differentiation induction medium was set to be 0.5 μg/ml in this study. Through alcian blue staining and real-time PCR, we found that chondrogenic specific cell markers expressed earlier in LTEs-treated cells than in LTEs-untreated cells (Fig. 1B, C). Next, we conducted tandem mass spectrometry and we found that ENPL expression was maximally increased between day 6 (blastema-phase, which displays the characteristics of mesenchymal stem cells) and day 12 (redifferentiation-phase) (Fig. 1D). Regarding intracellular mRNA expression of ENPL in T-MSCs, more induction of chondrogenic differentiation was associated with a more increase of ENPL expression (Fig. 1E).

ENPL promotes chondrogenic differentiation in T-MSCs

To determine the effect of ENPL on chondrogenic differentiation, we used luminespib (MedChemExpress, New Jersey, USA), an ENPL inhibitor by inhibiting the activation of ENPL (24). Furthermore, we investigated the expression of activating transcription factor 6 (ATF6), which is activated by ER stress and related to the expression of ENPL (25-29). We conducted experiments to investigate chondrogenesis specific cell markers. Results showed that target markers were expressed higher in cells treated with LTEs than in control cells not treated with LTEs (Fig. 2A, B). However, when cells were treated with luminespib, the expression of target markers was significantly suppressed at both mRNA and protein levels. Next, we overexpressed the ENPL gene in T-MSCs by transfecting cells with an ENPL overexpression vector. OV_0 meant that cells were cultured for 24 hours in a normal medium after transfection with the ENPL overexpression vector. OV_4, OV_8, and OV_12 indicated that cells were cultured for 4, 8, and 12 days in differentiation induction medium, respectively (Fig. 2C). Results showed that the vector was successfully transfected and that mRNA and protein expression levels of chondrogenesis-specific markers were significantly increased after differentiation induction.

ENPL inhibition decreases chondrogenic differentiation through ERK signaling

We conducted experiments to determine effects when ENPL was inactivated. ‘+I’ meant that cells were cultured in luminespib (inhibitor)-treated medium. When luminespib was used to treat cells, all target markers were significantly suppressed compared to those in inhibitor-untreated groups (Fig. 3A, B). In addition, results of alcian blue staining showed that GAGs accumulated relatively few in luminespib-treated groups (Fig. 3C). Finally, we investigated the mechanism of ERK signal pathway closely associated with ER stress during chondrogenesis (30, 31). Results revealed that phosphorylated ERK 1/2 showed fairly low levels in luminespib-untreated groups. On the contrary, ERK 1/2 phosphorylation was considerably high in luminespib-treated groups (Fig. 3D).

ENPL may promote chondrogenic differentiation of T-MSCs by inhibiting ERK 1/2 phosphorylation in an autocrine or a paracrine manner

After endogenous ENPL was verified to be able to induce chondrogenesis, exogenous ENPL (MyBioSource, Inc.) was used to investigate whether it could also induce differentiation. First of all, we determined whether exogenous ENPL was cytotoxic to T-MSCs through MTT assay. Results confirmed that ENPL did not induce cytotoxicity of T-MSCs except when it was used at a very concentration at 500 ng/ml (Fig. 4A). Next, to determine the effect of exogenous ENPL, cells were cultured in a differentiation induction medium excluding TGF-β. Alcian blue staining revealed that all ENPL-treated cells were stained more intensely than those not treated with ENPL (0 μg/ml) (Fig. 4B). In addition, we found that mRNA and protein expression levels of chondrogenesis-specific markers were increased in ENPL-treated groups (Fig. 4C, D). Moreover, the phosphorylation of ERK1/2 was suppressed by exogenous ENPL in a concentration-dependent manner (Fig. 4D). These results demonstrate that exogenous ENPL could also induce chondrogenic differentiation of cells by suppressing the ERK1/2 phosphorylation.


In this study, we paid attention to ER stress as the cause of an increase in ENPL. Commonly, ER stress is known to be the main cause of various diseases as it can induce abnormal responses of cells. However, it has been recently confirmed that appropriate and beneficial ER stress provides a significant signal in cells (25, 26). In addition, ER stress is known to be involved in the differentiation process of various cells such as chondrocytes (25, 26). When ER stress is induced by a specific stimulus, ATF6 localized in the membrane of the endoplasmic reticulum can act as a transcription factor in the nucleus that helps transcription of ER chaperone genes including ENPL (30-33). However, the initial mechanism as to how ENPL can bind to cells and how ENPL stimulus can initiate ER-stress has not been elucidated yet. In addition, certain cell signal pathways involved in chondrogenic differentiation remain controversial, especially the ERK signaling pathway (34-36). ERK can act in an activated or an inactivated state depending on MSCs derived from specific tissues. In this study, we confirmed that ERK phosphorylation was inhibited in cells that highly expressed chondrogenesis specific markers. It is meaningful for the authentication of the relationship between human ENPL and chondrogenic differentiation of MSCs in vitro.


Primary cell culture

Primary T-MSCs were obtained from Professor Jae-Ho Kim of Pusan National University Graduate School of Medicine. T-MSCs (passage 10) were usually cultured in α-MEM, no nucleosides medium (GibcoTM) supplemented with 10% fetal bovine serum (Capricorn Scientific) and 1X Antibiotic-Antimycotic (GibcoTM). The cells were incubated at 37°C and 5% CO2 conditions. The cells were detached by 0.25% Trypsin-EDTA (Capricorn Scientific) and then centrifuged at 2000 rpm for 5 min.

Induction of chondrogenic differentiation

T-MSCs were cultured in 60 mm cell culture dishes at 1 × 105 cells/dish in differentiation induction medium, which consisted of α-MEM containing 10% FBS, 1X Antibiotic-Antimycotic, 0.1 μM dexamethasone (Sigma-Aldrich), 50 μM L-Ascorbic acid (Sigma-Aldrich), 1% Sodium Pyruvate (Invitrogen), 10 ng/ml Trans-forming Growth Factor-β1 (TGF-β) human (Sigma-Aldrich) and 50 nM Insulin (Roche). The cells were incubated at 37°C and 5% CO2, and the differentiation induction medium was changed every 2 days. Especially, TGF-β1 was added up to 4 days of differentiation induction, after that, it was excepted from the medium components.

Preparation of lizard tail extracts (LTEs)

Lizards (Hemitheconyx caudicinctus) were purchased from Zools (Seoul, Korea). All experiments using lizard tail were approved by the Institutional Animal Care and Use Committee of Dong-A University. Also, we followed the guidelines of the Animal Care Committee of Dong-A University. After cutting the lizard’s tail to about 3 cm in length, we carefully peeled off only the skin of the cut tail. The peeled tail tissue was minced, placed in a homogenizer tube containing 1 ml 1X phosphate buffered saline (PBS, pH 7.4), and then homogenized using a homogenizer. The tissue was centrifuged at 4°C and 13000 rpm for 11 min, and then the supernatant was transferred into a new tube. To decompose the DNA and RNA in the supernatant, it is pulverized for 5 times at 2 watt, 2-second intervals using a sonicator and then centrifuged at 4°C and 13000 rpm for 11 min; the supernatant was transferred into a new tube by using a syringe filter (0.2 μm).

Cell cytotoxicity assay

3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 2-(4-iodo-phenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) assay were performed to verify the cells survival. T-MSCs were plated into 96 well plate at 1× 104 cells/dish in α-MEM containing 10% FBS, 1X Antibiotic-Anti-mycotic and then incubated for 24 hours. After that, the medium was removed, and a fresh medium containing LTEs or ENPL was added into the plate. After one more 24-hour incubation, the medium was gently removed and WST-1 reagent and MTT solution were prepared beforehand, and 110 μl of these solutions were dispensed into the wells, respectively. The cells were incubated at 37°C and 5% CO2 for 2 hours. Then, especially, the formazan, which formed in ENPL-treated experiment using an MTT reagent, was solubilized by adding 100 μl dimethyl sulfoxide (DMSO) into each well. The absorbance of formazan, which formed in both assays, was measured at 440 nm in quintuplicate.

Identification of proteins in extracts using tandem mass spectrometry

Tandem mass spectrometry was performed to identify each substance present in the LTEs. After separating the factors in LTEs obtained on the 6 and 12 days of regenerating through SDS-PAGE, we collected each selected protein spots and transferred them into a 1.5 ml tube. 200 μl of Sterile distilled water was added and stirred to wash the proteins three times for 10 min each. Then, 200 μl of 100 mM Ammonium bicarbonate/Acetonitrile (1:1 volume ratio) was added and then incubated for 30 min. Subsequently, 500 μl of Acetonitrile was added and stirred until the gel became faint and then dried for 15 min using a vacuum dryer. 0.25% Trypsin-EDTA 50 μl was added into a 1.5 ml tube containing dried gel pieces, and then the tube was allowed to stand on ice for 30 min. Subsequently, 20 μl of 50 mM Ammonium bicarbonate was added into the tube and then incubated at 37°C for 16 hours. Then, 20 μl of solution composed of 50% Acetonitrile, 47.5% water and 2.5% Trifluoroacetic acid, was added into the tube, incubated for 10 min, and then centrifuged at 10,000 rpm for 10 min. The supernatant was transferred into a new tube, and the sample was analyzed using mass spectrometry.

Alcian blue staining

Glycosaminoglycans (GAGs), which are formed from the deposition of cartilage-related proteoglycans, were detected through alcian blue staining. After the medium was removed, 1 ml 10% formalin was added into the plate and incubated for 20 min to fix the cells. After fixation, the cells were washed three times with 1X PBS and 1% alcian blue solution (Sigma-Aldrich) was added into each well, and then the plate was gently shaken for 1 hours. Subsequently, to distain the unnecessary stain, 0.1 M HCl was added. After the HCl was removed, the cells were washed twice with 1X PBS.

Cell transfection

For the overexpression of the ENPL gene, an ENPL overexpression vector that was prepared from the coding sequences of ENPL gene and pcDNA6/V5-His B vector was transfected into the T-MSCs. When the T-MSCs density exceeded 70%, transfection was performed according to the protocol of LipofectamineTM 2000 Transfection Reagent (Invitrogen).

Quantitative real-time polymerase chain reaction (qRT-PCR)


Western blotting

T-MSCs lysates were prepared in RIPA buffer (iNtRON Biotechnology, Gyeonggi, Republic of Korea) supplemented with protease inhibitors and phosphatase inhibitors (Thermo ScientificTM). Protein concentrations were measured using a PierceTM BCA Protein Assay Kit (Thermo ScientificTM) and proteins were separated by 10% SDS-PAGE. And then, proteins were transferred onto an NC membrane (Cytiva, formerly GE Healthcare) at 25 V and 400 mA for 45 min using a semi-dry transfer (Bio-Rad). Subsequently, the membrane was blocked with 5% or 7.5% skimmed milk and probed with primary antibodies to AGG (diluted 1:300, Proteintech Group, Inc.), COL2 (diluted 1:500, Proteintech Group, Inc.), SOX9 (diluted 1:100, Cell Signaling Technology Co.), ERK/p-ERK (diluted 1:1000, Cell Signaling Technology Co.) and GAPDH (diluted 1:1000, Enzo Life Sciences, Inc.) overnight at 4°C. The primary antibodies were detected by horseradish peroxidase (HRP)-conjugated secondary antibodies (diluted 1:5000, Enzo Life Sciences, Inc.) at 37°C for 2 hours, and blots were visualized by D-PlusTM ECL Pico System (DonginLS, Seoul, Republic of Korea).

Statistical analysis

All experiments were replicated at least three times. The results were presented as mean ± SEM, and statistical analysis was performed using GraphPad Prism 5.0 (GraphPad Software). The significance of difference was evaluated by t-test between control and experimental groups. The P-value < 0.05 was considered significant.


This work was supported by the National Research Foundation of Korea (NRF-2020R1F1A1070475) and the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM9952213).


The authors have no conflicting interests.

Fig. 1. LTEs induce the expression of chondrogenic specific cell markers in T-MSCs by regulating ENPL. (A) Potential cytotoxicity to T-MSCs according to the concentration of LTEs used for treatment was measured through WST-1 assay. (B) GAGs were relatively more accumulated in 0.5 μg/ml LTEs-treated cells, especially after day 8 (100× magnification). Scale bar = 100 μm. (C) Results of qRT-PCR showed relative mRNA levels of SOX9, AGG, COL2, and MMP13. (D) Up- or down-regulated proteins confirmed by tandem mass spectrometry of regenerating lizard tail on 6 days and 12 days, respectively. (E) Results of qRT-PCR showed relative mRNA expression of ENPL in T-MSCs during chondrogenic differentiation. *P < 0.05, **P < 0.01, ***P < 0.001 and ###P < 0.001.
Fig. 2. ENPL promotes chondrogenic differentiation in T-MSCs. Differentiation of T-MSCs into chondrocyte was induced for 8 days. DI, Differentiation Induction. (A) mRNA levels of ATF6 and ENPL determined by qRT-PCR. (B) mRNA and protein levels of chondrogenesis-specific markers were detected using qRT-PCR and Western blotting, respectively. (C) OV_0, 4, 8, and 12 meant that cells were cultured in differentiation medium for 0, 4, 8, and 12 days after transfection, respectively. Increased expression of ENPL mRNA in T-MSCs transfected by ENPL overexpression vector was determined. Relative mRNA and protein levels of chondrogenesis specific markers were detected using qRT-PCR and Western blotting, respectively. *P < 0.05, **P < 0.01 and ***P < 0.001.
Fig. 3. ENPL inhibition decreases chondrogenic differentiation through ERK signaling. ‘OV+I’ meant cells are cultured in inhibitor-treated medium after transfection. (A) mRNA levels of ATF6 and ENPL were detected by qRT-PCR. (B) Relative mRNA and protein levels of chon-drogenesis specific markers were detected using qRT-PCR and Western blotting, respectively. (C) Alcian blue staining was conducted to confirm GAGs deposition following transfection of ENPL overexpression vector (40× magnification). Scale bar = 200 μm. (D) Protein levels of phosphorylated ERK were detected by Western blotting. *P < 0.05, **P < 0.01 and ***P < 0.001.
Fig. 4. ENPL may promote chondrogenic differentiation of T-MSCs by inhibiting ERK 1/2 phosphorylation in an autocrine or a para-crine manner. (A) Potential cytotoxicity of ENPL to T-MSCs was measured through MTT assay. (B) Alcian blue staining was conducted to confirm GAGs deposition after treatment with exogenous ENPL (100× magnification). Scale bar = 100 μm. (C) mRNA levels of chondrogenesis specific markers were detected using qRT-PCR. (D) Protein levels of chondrogenesis specific markers and phosphorylated ERK1/2 were detected by Western blotting. DI, Differentiation induction. *P < 0.05, **P < 0.01 and ***P < 0.001. P > 0.05 is indicated by “ns” for not significant.
  1. Secunda R, Vennila R, Mohanashankar AM, Rajasundari M, Jeswanth S and Surendran R (2015) Isolation, expansion and characterisation of mesenchymal stem cells from human bone marrow, adipose tissue, umbilical cord blood and matrix: a comparative study. Cytotechnology 67, 793-807
    Pubmed KoreaMed CrossRef
  2. Araña M, Mazo M, Aranda P, Pelacho B and Prosper F (2013) Adipose tissue-derived mesenchymal stem cells: isolation, expansion, and characterization. Methods Mol Biol 1036, 47-61
    Pubmed CrossRef
  3. Mosna F, Sensebé L and Krampera M (2010) Human bone marrow and adipose tissue mesenchymal stem cells: a user's guide. Stem Cells Dev 19, 1449-1470
    Pubmed CrossRef
  4. Green JD, Tollemar V, Dougherty M et al (2015) Multifaceted signaling regulators of chondrogenesis: Implications in cartilage regeneration and tissue engineering. Genes Dis 2, 307-327
    Pubmed KoreaMed CrossRef
  5. Lam ATL, Reuveny S and Oh SK (2020) Human mesenchymal stem cell therapy for cartilage repair: review on isolation, expansion, and constructs. Stem Cell Res 44, 101738
    Pubmed CrossRef
  6. Chen YC, Chang YW, Tan KP, Shen YS, Wang YH and Chang CH (2018) Can mesenchymal stem cells and their conditioned medium assist inflammatory chondrocytes recovery?. PLoS One 13, e0205563
    Pubmed KoreaMed CrossRef
  7. Richardson SM, Kalamegam G, Pushparaj PN et al (2016) Mesenchymal stem cells in regenerative medicine: Focus on articular cartilage and intervertebral disc regeneration. Methods 99, 69-80
    Pubmed CrossRef
  8. Strioga M, Viswanathan S, Darinskas A, Slaby O and Michalek J (2012) Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev 21, 2724-2752
    Pubmed CrossRef
  9. Oh SY, Choi YM, Kim HY et al (2019) Application of tonsil-derived mesenchymal stem cells in tissue regeneration: concise review. Stem Cells 37, 1252-1260
    Pubmed KoreaMed CrossRef
  10. Ryu KH, Cho KA, Park HS et al (2012) Tonsil-derived me-senchymal stromal cells: evaluation of biologic, immunologic and genetic factors for successful banking. Cytotherapy 14, 1193-1202
    Pubmed CrossRef
  11. Somoza RA, Welter JF, Correa D and Caplan AI (2014) Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations. Tissue Eng Part B Rev 20, 596-608
    Pubmed KoreaMed CrossRef
  12. Kim H, Park S, Kim K, Ku S, Seo J and Roh S (2019) Enterococcus faecium L-15 cell-free extract improves the chondrogenic differentiation of human dental pulp stem cells. Int J Mol Sci 20, 624
    Pubmed KoreaMed CrossRef
  13. Deng Y, Lei G, Lin Z, Yang Y, Lin H and Tuan RS (2019) Engineering hyaline cartilage from mesenchymal stem cells with low hypertrophy potential via modulation of culture conditions and Wnt/β-catenin pathway. Biomaterials 192, 569-578
    Pubmed KoreaMed CrossRef
  14. Alibardi L (2018) Tail regeneration reduction in lizards after repetitive amputation or cauterization reflects an increase of immune cells in blastemas. Zool Res 39, 413-423
    Pubmed KoreaMed CrossRef
  15. Moghanjoghi SM, Ganjibakhsh M, Gohari NS et al (2018) Establishment and characterization of rough-tailed gecko original tail cells. Cytotechnology 70, 1337-1347
    Pubmed KoreaMed CrossRef
  16. Alibardi L (2015) Original and regenerating lizard tail cartilage contain putative resident stem/progenitor cells. Micron 78, 10-18
    Pubmed CrossRef
  17. Szarek D, Marycz K, Lis A et al (2016) Lizard tail spinal cord: a new experimental model of spinal cord injury without limb paralysis. FASEB J 30, 1391-403
    Pubmed CrossRef
  18. Bae KS, Kim SY, Park SY et al (2014) Identification of lactoferrin as a human dedifferentiation factor through the studies of reptile tissue regeneration mechanisms. J Microbiol Biotechnol 24, 869-878
    Pubmed CrossRef
  19. Marzec M, Eletto D and Argon Y (2012) GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim Biophys Acta 1823, 774-787
    Pubmed KoreaMed CrossRef
  20. Lambrecht S, Juchtmans N and Elewaut D (2014) Heat-shock proteins in stromal joint tissues: innocent bystanders or disease-initiating proteins?. Rheumatology (Oxford) 53, 223-232
    Pubmed CrossRef
  21. Ghiasi SM, Dahlby T, Hede Andersen C et al (2019) Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling. Diabetes 68, 747-760
    Pubmed KoreaMed CrossRef
  22. Almalki SG and Agrawal DK (2016) Effects of matrix metalloproteinases on the fate of mesenchymal stem cells. Stem Cell Res Ther 7, 129
    Pubmed KoreaMed CrossRef
  23. Fan Z, Tardif G, Hum D, Duval N, Pelletier JP and Martel- Pelletier J (2009) Hsp90{beta} and p130(cas): novel regulatory factors of MMP-13 expression in human osteoarthritic chondrocytes. Ann Rheum Dis 68, 976-982
    Pubmed CrossRef
  24. Chatterjee S, Bhattacharya S, Socinski MA and Burns TF (2016) HSP90 inhibitors in lung cancer: promise still unfulfilled. Clin Adv Hematol Oncol 14, 346-356
  25. Hughes A, Oxford AE, Tawara K, Jorcyk CL and Oxford JT (2017) Endoplasmic reticulum stress and unfolded protein response in cartilage pathophysiology; contributing factors to apoptosis and osteoarthritis. Int J Mol Sci 18, 665
    Pubmed KoreaMed CrossRef
  26. Kondo S, Saito A, Asada R, Kanemoto S and Imaizumi K (2011) Physiological unfolded protein response regulated by OASIS family members, transmembrane bZIP transcription factors. IUBMB Life 63, 233-239
    Pubmed CrossRef
  27. Meyer BA and Doroudgar S (2020) ER stress-induced secretion of proteins and their extracellular functions in the heart. Cells 9, 2066
    Pubmed KoreaMed CrossRef
  28. Gallagher CM and Walter P (2016) Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress. Elife 5, e11880
    Pubmed KoreaMed CrossRef
  29. Lee AS (2014) Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer 14, 263-276
    Pubmed KoreaMed CrossRef
  30. Yang F, Tang XY, Liu H and Jiang ZW (2016) Inhibition of mitogen-activated protein kinase signaling pathway sensi-tizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis. Oncol Rep 35, 2113-2120
    Pubmed CrossRef
  31. Darling NJ and Cook SJ (2014) The role of MAPK signalling pathways in the response to endoplasmic reticulum stress. Biochim Biophys Acta 1843, 2150-2163
    Pubmed CrossRef
  32. Haze K, Yoshida H, Yanagi H, Yura T and Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10, 3787-3799
    Pubmed KoreaMed CrossRef
  33. Shen C, Jiang T, Zhu B et al (2018) In vitro culture expansion impairs chondrogenic differentiation and the therapeutic effect of mesenchymal stem cells by regulating the unfolded protein response. J Biol Eng 12, 26
    Pubmed KoreaMed CrossRef
  34. Li J, Zhao Z, Liu J et al (2010) MEK/ERK and p38 MAPK regulate chondrogenesis of rat bone marrow mesenchymal stem cells through delicate interaction with TGF-β1/Smads pathway. Cell Prolif 43, 333-343
    Pubmed KoreaMed CrossRef
  35. Leppä S, Saffrich R, Ansorge W and Bohmann D (1998) Differential regulation of c-Jun by ERK and JNK during PC12 cell differentiation. EMBO J 17, 4404-4413
    Pubmed KoreaMed CrossRef
  36. Luo S, Shi Q, Li W, Wu W and Zha Z (2020) ITGB1 promotes the chondrogenic differentiation of human adipose-derived mesenchymal stem cells by activating the ERK signaling. J Mol Histol 51, 729-739
    Pubmed CrossRef

This Article

Cited By Articles
  • CrossRef (0)

Author ORCID Information

Funding Information


Social Network Service