Study on the protective mechanism of autophagy on cartilage by magnesium sulfate_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

CHEN Rong ¹ , ZHOU Xue ² , YIN Shaomei ² , LU Zeyu ² , NIE Jinpeng ² , ZHOU Wencheng ² ,  LIU Xinghui ³

1. Department of Traumatic Orthopedics, the People’s Hospital of Shiyan, Affiliated to Hubei University of Medicine, Shiyan Hubei, 442000, P.R.China;
2. The Fourth Hospital of Clinical Medicine, Hubei University of Medicine, Shiyan Hubei, 442000, P.R.China;
3. Department of Anatomy, Hubei University of Medicine, Shiyan Hubei, 442000, P.R.China;

Corresponding author：

LIU Xinghui, Email: liuxinghui555@163.com

Keywords：

Post-traumatic osteoarthritis; autophagy; cartilage injury; magnesium sulfate; rabbit

DOI：

10.7507/1002-1892.201804015

Video：

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ObjectiveTo investigate the mechanism of magnesium sulfate in protecting rabbit cartilage by initiating autophagy.MethodsTwenty-four adult female New Zealand rabbits were used to prepare post-traumatic osteoarthritis (PTOA) models by anterior cruciate ligament transection. Then, the PTOA models were randomly divided into PTOA group, distilled water group, and magnesium sulfate group, with 8 rabbits in each group. Immediately after operation, the distilled water group and the magnesium sulfate group were injected with 0.5 mL distilled water and 20 mmol/L magnesium sulfate solution in the joint cavity 3 times a week for 4 weeks, respectively. The PTOA group was not treated. The general condition of the animals was observed after operation. After 4 weeks, the expressions of tumor necrosis factor α (TNF-α) and collagen typeⅡ in the joint fluid and the expression of collagen type Ⅱ in venous blood were detected by ELISA assay. The protein expressions of transient receptor potential channel vanilloid 5 (TRPV5) and microtubule associated protein 1 light chain 3 (LC3; LC3-Ⅱ/LC3-Ⅰ) in femoral cartilage were detected by Western blot. The mRNA expressions of interleukin 1β (IL-1β), TNF-α, matrix metalloproteinases 3 (MMP-3) in synovial tissue and collagen type Ⅱ, Aggrecan (AGN), SOX9 in cartilage tissue were detected by real-time fluorescence quantitative PCR. Cartilage tissue sections were stained with HE staining, Masson staining, and Alcian blue staining and scored according to the modified histological osteoarthritis (OA) score.ResultsAll animals survived until the experiment was completed. Compared with the other two groups, the expression of TNF-α in joint effusion and collagen type Ⅱ in joint effusion and venous blood were decreased in magnesium sulfate group; the protein expression of TRPV5 decreased, and the ratio of LC3-Ⅱ/LC3-Ⅰ increased significantly; the mRNA expressions of IL-1β, TNF-α, and MMP-3 in synovial tissue were decreased, and the mRNA expressions of collagen type Ⅱ, AGN, and SOX9 in cartilage tissue were increased; OA scores also decreased significantly. All differences were statistically significant (P<0.05). There was no significant difference in the above indicators between the PTOA group and the distilled water group (P>0.05).ConclusionIntra-articular injection of magnesium sulfate can reduce intra-articular inflammation, reduce the loss of collagen type Ⅱ and AGN, and is beneficial to cartilage regeneration in rabbits. The mechanism may be related to the initiation of chondroautophagy by inhibiting the calcium channel TRPV5.

Citation： CHEN Rong, ZHOU Xue, YIN Shaomei, LU Zeyu, NIE Jinpeng, ZHOU Wencheng, LIU Xinghui. Study on the protective mechanism of autophagy on cartilage by magnesium sulfate. Chinese Journal of Reparative and Reconstructive Surgery, 2018, 32(10): 1340-1345. doi: 10.7507/1002-1892.201804015 Copy

1.	Brown TD, Johnston RC, Saltzman CL, et al. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma, 2006, 20(10): 739-744.
2.	Aurich M, Koenig V, Hofmann G. Comminuted intraarticular fractures of the tibial plateau lead to posttraumatic osteoarthritis of the knee: Current treatment review. Asian J Surg, 2018, 41(2): 99-105.
3.	Schenker ML, Mauck RL, Ahn J, et al. Pathogenesis and prevention of posttraumatic osteoarthritis after intra-articular fracture. J Am Acad Orthop Surg, 2014, 22(1): 20-28.
4.	Cinque ME, Dornan GJ, Chahla J, et al. High rates of osteoarthritis develop after anterior cruciate ligament surgery: An analysis of 4108 patients. Am J Sports Med, 2018, 46(8): 2011-2019.
5.	Lieberthal J, Sambamurthy N, Scanzello CR. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage, 2015, 23(11): 1825-1834.
6.	Heard BJ, Barton KI, Chung M, et al. Single intra-articular dexamethasone injection immediately post-surgery in a rabbit model mitigates early inflammatory responses and post-traumatic osteoarthritis-like alterations. J Orthop Res, 2015, 33(12): 1826-1834.
7.	Lei GH, Zeng C, Xie DX, et al. Analgesic effect and safety of single-dose intra-articular magnesium after arthroscopic surgery: a systematic review and meta-analysis. Sci Rep, 2016, 30(6): 24-33.
8.	Lee CH, Wen ZH, Chang YC, et al. Intra-articular magnesium sulfate (MgSO4) reduces experimental osteoarthritis and nociception: association with attenuation of N-methyl-D-aspartate (NMDA) receptor subunit 1 phosphorylation and apoptosis in rat chondrocytes. Osteoarthritis Cartilage, 2009, 17(11): 1485-1493.
9.	Nielsen FH. Effects of magnesium depletion on inflammation in chronic disease. Curr Opin Clin Nutr Metab Care, 2014, 17(6): 525-530.
10.	Gruber HE, Ingram J, Norton HJ, et al. Alterations in growth plate and articular cartilage morphology are associated with reduced SOX9 localization in the magnesium-deficient rat. Biotech Histochem, 2004, 79(1): 45-52.
11.	Lee J, Cha SK, Sun TJ, et al. PIP2 activates TRPV5 and releases its inhibition by intracellular Mg²⁺. J Gen Physiol, 2005, 126(5): 439-451.
12.	Wei Y, Wang Y, Wang Y, et al. Transient receptor potential vanilloid 5 mediates Ca²⁺ influx and inhibits chondrocyte autophagy in a rat osteoarthritis model. Cell Physiol Biochem, 2017, 42(1): 319-332.
13.	Caramés B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum, 2010, 62(3): 791-801.
14.	Caramés B, Taniguchi N, Seino D, et al. Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection. Arthritis Rheum, 2012, 64(4): 1182-1192.
15.	Chang NJ, Lee KW, Chu CJ, et al. A preclinical assessment of early continuous passive motion and treadmill therapeutic exercises for generating chondroprotective effects after anterior cruciate ligament rupture. Am J Sports Med, 2017, 45(10): 2284-2293.
16.	Zeng C, Li H, Wei J, et al. Association between dietary magnesium intake and radiographic knee osteoarthritis. PLoS One, 2015, 10(5): e0127666.
17.	Qin B, Shi X, Samai PS, et al. Association of dietary magnesium intake with radiographic knee osteoarthritis: results from a population-based study. Arthritis Care Res (Hoboken), 2012, 64(9): 1306-1311.
18.	Lamhot VB, Khatib N, Ginsberg Y, et al. Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring. Am J Obstet Gynecol, 2015, 213(6): 851.e1-851.e8.
19.	Dou Y, Li N, Zheng Y, et al. Effects of fluctuant magnesium concentration on phenotype of the primary chondrocytes. J Biomed Mater Res A, 2014, 102(12): 4455-4463.
20.	Hagandora CK, Tudares MA, Almarza AJ. The effect of magnesium ion concentration on the fibrocartilage regeneration potential of goat costal chondrocytes. Ann Biomed Eng, 2012, 40(3): 688-696.
21.	Wang J, Liu Y, Zhou LJ, et al. Magnesium L-threonate prevents and restores memory deficits associated with neuropathic pain by inhibition of TNF-alpha. Pain Physician, 2013, 16(5): E563-E575.
22.	Ansari MY, Khan NM, Haqqi TM. A standardized extract of Butea monosperma (Lam.) flowers suppresses the IL-1β-induced expression of IL-6 and matrix-metalloproteases by activating autophagy in human osteoarthritis chondrocytes. Biomed Pharmacother, 2017, 96(1): 198-207.
23.	Tang Q, Zheng G, Feng Z, et al. Trehalose ameliorates oxidative stress-mediated mitochondrial dysfunction and ER stress via selective autophagy stimulation and autophagic flux restoration in osteoarthritis development. Cell Death Dis, 2017, 8(10): 81-95.
24.	Park JH, Choi SH, Kim H, et al. Doxorubicin regulates autophagy signals via accumulation of cytosolic Ca²⁺ in human cardiac progenitor cells. Int J Mol Sci, 2016, 17(10): 1680-1693.
25.	Egerbacher M, Wolfesberger B, Gabler C. In vitro evidence for effects of magnesium supplementation on quinolone-treated horse and dog chondrocytes. Vet Pathol, 2001, 38(2): 143-148.

1. Brown TD, Johnston RC, Saltzman CL, et al. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma, 2006, 20(10): 739-744.
2. Aurich M, Koenig V, Hofmann G. Comminuted intraarticular fractures of the tibial plateau lead to posttraumatic osteoarthritis of the knee: Current treatment review. Asian J Surg, 2018, 41(2): 99-105.
3. Schenker ML, Mauck RL, Ahn J, et al. Pathogenesis and prevention of posttraumatic osteoarthritis after intra-articular fracture. J Am Acad Orthop Surg, 2014, 22(1): 20-28.
4. Cinque ME, Dornan GJ, Chahla J, et al. High rates of osteoarthritis develop after anterior cruciate ligament surgery: An analysis of 4108 patients. Am J Sports Med, 2018, 46(8): 2011-2019.
5. Lieberthal J, Sambamurthy N, Scanzello CR. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage, 2015, 23(11): 1825-1834.
6. Heard BJ, Barton KI, Chung M, et al. Single intra-articular dexamethasone injection immediately post-surgery in a rabbit model mitigates early inflammatory responses and post-traumatic osteoarthritis-like alterations. J Orthop Res, 2015, 33(12): 1826-1834.
7. Lei GH, Zeng C, Xie DX, et al. Analgesic effect and safety of single-dose intra-articular magnesium after arthroscopic surgery: a systematic review and meta-analysis. Sci Rep, 2016, 30(6): 24-33.
8. Lee CH, Wen ZH, Chang YC, et al. Intra-articular magnesium sulfate (MgSO4) reduces experimental osteoarthritis and nociception: association with attenuation of N-methyl-D-aspartate (NMDA) receptor subunit 1 phosphorylation and apoptosis in rat chondrocytes. Osteoarthritis Cartilage, 2009, 17(11): 1485-1493.
9. Nielsen FH. Effects of magnesium depletion on inflammation in chronic disease. Curr Opin Clin Nutr Metab Care, 2014, 17(6): 525-530.
10. Gruber HE, Ingram J, Norton HJ, et al. Alterations in growth plate and articular cartilage morphology are associated with reduced SOX9 localization in the magnesium-deficient rat. Biotech Histochem, 2004, 79(1): 45-52.
11. Lee J, Cha SK, Sun TJ, et al. PIP2 activates TRPV5 and releases its inhibition by intracellular Mg²⁺. J Gen Physiol, 2005, 126(5): 439-451.
12. Wei Y, Wang Y, Wang Y, et al. Transient receptor potential vanilloid 5 mediates Ca²⁺ influx and inhibits chondrocyte autophagy in a rat osteoarthritis model. Cell Physiol Biochem, 2017, 42(1): 319-332.
13. Caramés B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum, 2010, 62(3): 791-801.
14. Caramés B, Taniguchi N, Seino D, et al. Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection. Arthritis Rheum, 2012, 64(4): 1182-1192.
15. Chang NJ, Lee KW, Chu CJ, et al. A preclinical assessment of early continuous passive motion and treadmill therapeutic exercises for generating chondroprotective effects after anterior cruciate ligament rupture. Am J Sports Med, 2017, 45(10): 2284-2293.
16. Zeng C, Li H, Wei J, et al. Association between dietary magnesium intake and radiographic knee osteoarthritis. PLoS One, 2015, 10(5): e0127666.
17. Qin B, Shi X, Samai PS, et al. Association of dietary magnesium intake with radiographic knee osteoarthritis: results from a population-based study. Arthritis Care Res (Hoboken), 2012, 64(9): 1306-1311.
18. Lamhot VB, Khatib N, Ginsberg Y, et al. Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring. Am J Obstet Gynecol, 2015, 213(6): 851.e1-851.e8.
19. Dou Y, Li N, Zheng Y, et al. Effects of fluctuant magnesium concentration on phenotype of the primary chondrocytes. J Biomed Mater Res A, 2014, 102(12): 4455-4463.
20. Hagandora CK, Tudares MA, Almarza AJ. The effect of magnesium ion concentration on the fibrocartilage regeneration potential of goat costal chondrocytes. Ann Biomed Eng, 2012, 40(3): 688-696.
21. Wang J, Liu Y, Zhou LJ, et al. Magnesium L-threonate prevents and restores memory deficits associated with neuropathic pain by inhibition of TNF-alpha. Pain Physician, 2013, 16(5): E563-E575.
22. Ansari MY, Khan NM, Haqqi TM. A standardized extract of Butea monosperma (Lam.) flowers suppresses the IL-1β-induced expression of IL-6 and matrix-metalloproteases by activating autophagy in human osteoarthritis chondrocytes. Biomed Pharmacother, 2017, 96(1): 198-207.
23. Tang Q, Zheng G, Feng Z, et al. Trehalose ameliorates oxidative stress-mediated mitochondrial dysfunction and ER stress via selective autophagy stimulation and autophagic flux restoration in osteoarthritis development. Cell Death Dis, 2017, 8(10): 81-95.
24. Park JH, Choi SH, Kim H, et al. Doxorubicin regulates autophagy signals via accumulation of cytosolic Ca²⁺ in human cardiac progenitor cells. Int J Mol Sci, 2016, 17(10): 1680-1693.
25. Egerbacher M, Wolfesberger B, Gabler C. In vitro evidence for effects of magnesium supplementation on quinolone-treated horse and dog chondrocytes. Vet Pathol, 2001, 38(2): 143-148.

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