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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2016

Open Access 01-12-2016 | Research article

The protective role of autophagy in experimental osteoarthritis, and the therapeutic effects of Torin 1 on osteoarthritis by activating autophagy

Authors: Ni-Tao Cheng, Ai Guo, Hai Meng

Published in: BMC Musculoskeletal Disorders | Issue 1/2016

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Abstract

Background

Recent studies have shown that autophagy was associated with the development of osteoarthritis (OA), the purpose of this research was to determine the exact role of autophagy in OA and investigate effective therapeutic drugs to inhibit the pathological progression of OA.

Methods

In this study, a cellular OA model was generated by stimulating SW1353 cells with IL-1β and a rabbit OA model was established by intra-articular injection of collagenase, followed by treatment with Torin 1 or 3-Methyladenine (3-MA). The mRNA expression levels of VEGF, MMP-13 and TIMP-1 were determined by quantitative real-time PCR. The caitilage degeneration was examined by histological evaluation, chondrocytes degeneration and autophagosomes were observed by transmission electron microscopy. Expression levels of Beclin-1 and LC3 were evaluated by western blotting and immunofluorescence.

Results

The degeneration of SW 1353 cells, cartilage and chondrocytes was related to the loss of autophagy in experimental OA. 3-MA increased the severity of degeneration of cells and cartilage by autophagy inhibition, while Torin 1 reduced that by autophagy activation.

Conclusions

The loss of autophagy is linked with the experimental OA and autophagy may play a protective role in the pathogenesis of OA. Treatment of Torin 1 can inhibit the degenerative changes of experimental OA by activating autophagy and it may be a useful therapeutic drug for OA.
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Literature
1.
Mizushima N. Physiological functions of autophagy. Curr Top Microbiol Immunol. 2009;335:71–84.PubMed
2.
3.
4.
5.
Dwivedi M, Ahnn J. Autophagy--is it a preferred route for lifespan extension? BMB Rep. 2009;42:62–71.CrossRefPubMed
6.
7.
Young CN, Sinadinos A, Lefebvre A, Chan P, Arkle S, Vaudry D, et al. A novel mechanism of autophagic cell death in dystrophic muscle regulated by P2RX7 receptor large-pore formation and HSP90. Autophagy. 2015;11:113–30.CrossRefPubMedPubMedCentral
8.
Tang B, Li Q, Zhao XH, Wang HG, Li N, Fang Y, et al. Shiga toxins induce autophagic cell death in intestinal epithelial cells via the endoplasmic reticulum stress pathway. Autophagy. 2015;11:344–54.CrossRefPubMedPubMedCentral
9.
10.
Chiu HW, Chen YA, Ho SY, Wang YJ. Arsenic trioxide enhances the radiation sensitivity of androgen-dependent and -independent human prostate cancer cells. PLoS One. 2012;7, e31579.CrossRefPubMedPubMedCentral
11.
12.
Santambrogio L, Cuervo AM. Chasing the elusive mammalian microautophagy. Autophagy. 2011;7:652–4.CrossRefPubMed
13.
Kaushik S, Bandyopadhyay U, Sridhar S, Kiffin R, Martinez-Vicente M, Kon M, et al. Chaperone-mediated autophagy at a glance. J Cell Sci. 2011;124:495–9.CrossRefPubMedPubMedCentral
14.
15.
Kabeya Y, Kamada Y, Baba M, Takikawa H, Sasaki M, Ohsumi Y. Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol Biol Cell. 2005;16:2544–53.CrossRefPubMedPubMedCentral
16.
Kuma A, Mizushima N. Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin Cell Dev Biol. 2010;21:683–90.CrossRefPubMed
17.
Ohsumi Y, Mizushima N. Two ubiquitin-like conjugation systems essential for autophagy. Semin Cell Dev Biol. 2004;15:231–6.CrossRefPubMed
18.
Furuya N, Yu J, Byfield M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy. 2005;1:46–52.CrossRefPubMed
19.
Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–6.CrossRefPubMed
20.
Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90:1383–435.CrossRefPubMed
21.
22.
Kim HJ, So HS, Lee JH, Park C, Lee JB, Youn MJ, et al. Role of proinflammatory cytokines in cisplatin-induced vestibular hair cell damage. Head Neck. 2008;30:1445–56.CrossRefPubMed
23.
Garvican ER, Vaughan-Thomas A, Redmond C, Clegg PD. MT3-MMP (MMP-16) is downregulated by in vitro cytokine stimulation of cartilage, but unaltered in naturally occurring equine osteoarthritis and osteochondrosis. Connect Tissue Res. 2008;49:62–7.CrossRefPubMed
24.
Takahashi K, Goomer RS, Harwood F, Kubo T, Hirasawa Y, Amiel D. The effects of hyaluronan on matrix metalloproteinase-3 (MMP-3), interleukin-1beta(IL-1beta), and tissue inhibitor of metalloproteinase-1 (TIMP-1) gene expression during the development of osteoarthritis. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 1999;7:182–90.CrossRefPubMed
25.
Dejica VM, Mort JS, Laverty S, Antoniou J, Zukor DJ, Tanzer M, et al. Increased type II collagen cleavage by cathepsin K and collagenase activities with aging and osteoarthritis in human articular cartilage. Arthritis Res Ther. 2012;14:R113.CrossRefPubMedPubMedCentral
26.
Wei T, Kulkarni NH, Zeng QQ, Helvering LM, Lin X, Lawrence F, et al. Analysis of early changes in the articular cartilage transcriptisome in the rat meniscal tear model of osteoarthritis: pathway comparisons with the rat anterior cruciate transection model and with human osteoarthritic cartilage. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 2010;18:992–1000.CrossRefPubMed
27.
Adaes S, Ferreira-Gomes J, Mendonca M, Almeida L, Castro-Lopes JM, Neto FL. Injury of primary afferent neurons may contribute to osteoarthritis induced pain: an experimental study using the collagenase model in rats. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 2015;23:914-24.
28.
Kikuchi T, Sakuta T, Yamaguchi T. Intra-articular injection of collagenase induces experimental osteoarthritis in mature rabbits. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 1998;6:177–86.CrossRefPubMed
29.
Lahm A, Kasch R, Mrosek E, Spank H, Erggelet C, Esser J, et al. Semiquantitative analysis of ECM molecules in the different cartilage layers in early and advanced osteoarthritis of the knee joint. Histol Histopathol. 2012;27:609–15.PubMed
30.
Zhang M, Zhang J, Lu L, Qiu Z-Y, Zhang X, Yu S-B, et al. Enhancement of chondrocyte autophagy is an early response in the degenerative cartilage of the temporomandibular joint to biomechanical dental stimulation. Apoptosis : an international journal on programmed cell death. 2013;18:423–34.CrossRef
31.
Almonte-Becerril M, Navarro-Garcia F, Gonzalez-Robles A, Vega-Lopez MA, Lavalle C, Kouri JB. Cell death of chondrocytes is a combination between apoptosis and autophagy during the pathogenesis of Osteoarthritis within an experimental model. Apoptosis : an international journal on programmed cell death. 2010;15:631–8.CrossRef
32.
Carames B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010;62:791–801.CrossRefPubMedPubMedCentral
33.
Wu C, Zheng J, Yao X, Shan H, Li Y, Xu P, et al. Defective autophagy in chondrocytes with Kashin-Beck disease but higher than osteoarthritis. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 2014;22:1936–46.CrossRefPubMed
34.
Ranstam J. Repeated measurements, bilateral observations and pseudoreplicates, why does it matter? Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 2012;20:473–5.CrossRefPubMed
35.
Mankin HJ, Johnson ME, Lippiello L. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. III. Distribution and metabolism of amino sugar-containing macromolecules. J Bone Joint Surg Am. 1981;63:131–9.PubMed
36.
Best TM, Dexter WW. Osteoarthritis--a silent problem that needs our attention! Curr Sports Med Rep. 2013;12:138–9.CrossRefPubMed
37.
Hulth A, Lindberg L, Telhag H. Experimental osteoarthritis in rabbits. Preliminary report. Acta Orthop Scand. 1970;41:522–30.CrossRefPubMed
38.
Nordback S, Erba P, Wehrli L, Raffoul W, Egloff DV. Trapeziectomy and tendon suspension with or without a mitek anchor fixation in the thumb basal joint osteoarthritis. J Hand Surg Eur Vol. 2012;37:625–31.CrossRefPubMed
39.
Huh JE, Park YC, Seo BK, Lee JD, Baek YH, Choi DY, et al. Cartilage Protective and Chondrogenic Capacity of WIN-34B, a New Herbal Agent, in the Collagenase-Induced Osteoarthritis Rabbit Model and in Progenitor Cells from Subchondral Bone. Evid Based Complement Alternat Med: eCAM. 2013;2013:527561.PubMedPubMedCentral
40.
Miyauchi S, Machida A, Onaya J, Sakamoto T, Tokuyasu K, Iwata H. Alterations of proteoglycan synthesis in rabbit articular cartilage induced by intra-articular injection of papain. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 1993;1:253–62.CrossRefPubMed
41.
Haas S, Straub RH. Disruption of rhythms of molecular clocks in primary synovial fibroblasts of patients with osteoarthritis and rheumatoid arthritis, role of IL-1beta/TNF. Arthritis Res Ther. 2012;14:R122.CrossRefPubMedPubMedCentral
42.
Kojima T. Role of cleavage of type II collagen by collagenase in osteoarthritis and its progression. Clin Calcium. 2004;14:90–3.PubMed
43.
Uchimura T, Foote AT, Smith EL, Matzkin EG, Zeng L. Insulin-Like Growth Factor II (IGF-II) Inhibits IL-1beta-Induced Cartilage Matrix Loss and Promotes Cartilage Integrity in Experimental Osteoarthritis. J Cell Biochem. 2015;116:2858–69.CrossRefPubMed
44.
Qin J, Shang L, Ping AS, Li J, Li XJ, Yu H, et al. TNF/TNFR signal transduction pathway-mediated anti-apoptosis and anti-inflammatory effects of sodium ferulate on IL-1beta-induced rat osteoarthritis chondrocytes in vitro. Arthritis Res Ther. 2012;14:R242.CrossRefPubMedPubMedCentral
45.
Adaes S, Mendonca M, Santos TN, Castro-Lopes JM, Ferreira-Gomes J, Neto FL. Intra-articular injection of collagenase in the knee of rats as an alternative model to study nociception associated with osteoarthritis. Arthritis Res Ther. 2014;16:R10.CrossRefPubMedPubMedCentral
46.
Yang L, Guo A, Gu JC. c-Jun N-terminal kinase and nuclear factor kappaB mediate nitric oxide-induced expression of matrix metalloproteinase-13. Int Orthop. 2011;35:1261–6.CrossRefPubMedPubMedCentral
47.
48.
Yang RT, Zhang C, Liu Y, Zhou HH, Li ZB. Autophagy prior to chondrocyte cell death during the degeneration of Meckel's cartilage. Anat Rec. 2012;295:734–41.CrossRef
49.
Gruber HE, Hoelscher GL, Ingram JA, Bethea S, Hanley Jr EN. Autophagy in the Degenerating Human Intervertebral Disc: In Vivo Molecular and Morphological Evidence, and Induction of Autophagy in Cultured Annulus Cells Exposed to Proinflammatory Cytokines-Implications for Disc Degeneration. Spine. 2015;40:773–82.CrossRefPubMed
50.
Lotz M, Carames B. Autophagy: a new therapeutic target in cartilage injury and osteoarthritis. J Am Acad Orthop Surg. 2012;20:261–2.CrossRefPubMed
51.
Carames B, Hasegawa A, Taniguchi N, Miyaki S, Blanco FJ, Lotz M. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis. 2012;71:575–81.CrossRefPubMedPubMedCentral
Metadata
Title
The protective role of autophagy in experimental osteoarthritis, and the therapeutic effects of Torin 1 on osteoarthritis by activating autophagy
Authors
Ni-Tao Cheng
Ai Guo
Hai Meng
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2016
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-016-0995-x

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