Protocatechuic acid attenuates anterior cruciate ligament transection‑induced osteoarthritis by suppressing osteoclastogenesis

Zhang,Jialin; Fu,Bin; Chen,Xiaolei; Chen,Desheng; Yang,Hao

doi:10.3892/etm.2019.8189

Protocatechuic acid attenuates anterior cruciate ligament transection‑induced osteoarthritis by suppressing osteoclastogenesis

Authors:
- Jialin Zhang
- Bin Fu
- Xiaolei Chen
- Desheng Chen
- Hao Yang
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Affiliations: Department of Orthopedics, General Hospital of Ningxia Medical University, Ningxia, Gansu 750004, P.R. China, Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
Published online on: November 12, 2019 https://doi.org/10.3892/etm.2019.8189
Pages: 232-240
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteoarthritis (OA) is related to over‑proliferation or differentiation of osteoclasts. Although protocatechuic acid (PCA) has been identified to inhibit osteoclast differentiation and stimulate apoptosis in mature osteoclasts, whether it can relieve OA is still unknown. The present study aimed to investigate the effect of PCA on anterior cruciate ligament transection (ACLT)‑induced OA and the potential mechanisms of action behind this effect. ACLT was performed on rats, which were then treated with or without PCA. C‑terminal telopeptide of type I collagen (CTX‑I) and CTX‑II were tested in knee joint protein extracts by ELISA. Damage to cartilage was evaluated using Safranin‑O/Fast Green staining. Osteoclast‑related gene and protein expression was assessed through reverse transcription‑quantitative PCR and western blotting. Tartrate‑resistant acid phosphatase (TRAP) staining and functional bone resorption pit assays were performed using RAW264.7 murine macrophage cells to determine the effects of PCA on osteoclastic formation and function, respectively, in vitro. Finally, the activity of osteoclastogenesis‑related signaling pathways was evaluated by western blotting. Levels of CTX‑II were relatively decreased and Safranin‑O/fast green staining indicated milder changes in the articular cartilage in the PCA treatment group. PCA downregulated osteoclast specific markers and suppressed receptor activator of nuclear factor‑κB ligand‑induced formation of TRAP‑positive multinucleated cells, bone‑resorption and pit formation. Mitogen‑activated protein kinase (MAPK) and Akt signaling as well as the downstream factors, were downregulated by PCA. In conclusion, the present study demonstrated that PCA attenuated ACLT‑induced OA by suppressing osteoclastogenesis by inhibiting the MAPK, ATK and NF‑κB signaling pathways.

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1	Lluch Girbés E, Nijs J, Torres-Cueco R and López Cubas C: Pain treatment for patients with osteoarthritis and central sensitization. Phys Ther. 93:842–851. 2013. View Article : Google Scholar : PubMed/NCBI
2	Clouet J, Vinatier C, Merceron C, Pot-vaucel M, Maugars Y, Weiss P, Grimandi G and Guicheux J: From osteoarthritis treatments to future regenerative therapies for cartilage. Drug Discov Today. 14:913–925. 2009. View Article : Google Scholar : PubMed/NCBI
3	Suri S and Walsh DA: Osteochondral alterations in osteoarthritis. Bone. 51:204–211. 2012. View Article : Google Scholar : PubMed/NCBI
4	Boyle WJ, Simonet WS and Lacey DL: Osteoclast differentiation and activation. Nature. 423:337–342. 2003. View Article : Google Scholar : PubMed/NCBI
5	Rodan GA and Martin TJ: Therapeutic approaches to bone diseases. Science. 289:1508–1514. 2000. View Article : Google Scholar : PubMed/NCBI
6	Koh YH, Hong SH, Kang HS, Chung CY, Koo KH, Chung HW, Cha JH and Son KR: The effects of bone turnover rate on subchondral trabecular bone structure and cartilage damage in the osteoarthritis rat model. Rheumatol Int. 30:1165–1171. 2010. View Article : Google Scholar : PubMed/NCBI
7	Strassle BW, Mark L, Leventhal L, Piesla MJ, Jian Li X, Kennedy JD, Glasson SS and Whiteside GT: Inhibition of osteoclasts prevents cartilage loss and pain in a rat model of degenerative joint disease. Osteoarthritis Cartilage. 18:1319–1328. 2010. View Article : Google Scholar : PubMed/NCBI
8	Bagi CM, Berryman E, Zakur DE, Wilkie D and Andresen CJ: Effect of antiresorptive and anabolic bone therapy on development of osteoarthritis in a posttraumatic rat model of OA. Arthritis Res Ther. 17:3152015. View Article : Google Scholar : PubMed/NCBI
9	Siebelt M, Waarsing JH, Groen HC, Müller C, Koelewijn SJ, de Blois E, Verhaar JA, de Jong M and Weinans H: Inhibited osteoclastic bone resorption through alendronate treatment in rats reduces severe osteoarthritis progression. Bone. 66:163–170. 2014. View Article : Google Scholar : PubMed/NCBI
10	Zhao C, Liu Q and Wang K: Artesunate attenuates ACLT-induced osteoarthritis by suppressing osteoclastogenesis and aberrant angiogenesis. Biomed Pharmacother. 96:410–416. 2017. View Article : Google Scholar : PubMed/NCBI
11	Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, et al: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 95:3597–3602. 1998. View Article : Google Scholar : PubMed/NCBI
12	Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, et al: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 93:165–176. 1998. View Article : Google Scholar : PubMed/NCBI
13	Zhao Q, Wang X, Liu Y, He A and Jia R: NFATc1: Functions in osteoclasts. Int J Biochem Cell Biol. 42:576–579. 2010. View Article : Google Scholar : PubMed/NCBI
14	Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, et al: Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 3:889–901. 2002. View Article : Google Scholar : PubMed/NCBI
15	Kakkar S and Bais S: A review on protocatechuic acid and its pharmacological potential. ISRN Pharmacol. 2014:9529432014. View Article : Google Scholar : PubMed/NCBI
16	Li XC, Wang XZ, Chen DF and Chen SZ: Antioxidant activity and mechanism of protocatechuic acid in vitro. Funct Foods Health Dis. 1:232–244. 2011.
17	Mahadevan N, Shival i and Kamboj P: Hibiscus sabdariffa Linn.-An overview. Nat Prod Radiance. 8:77–83. 2009.
18	Tanaka T, Tanaka T and Tanaka M: Potential cancer chemopreventive activity of protocatechuic acid. J Exp Clin Med. 3:27–33. 2011. View Article : Google Scholar
19	Lende AB, Kshirsagar AD, Deshpande AD, Muley MM, Patil RR, Bafna PA and Naik SR: Anti-inflammatory and analgesic activity of protocatechuic acid in rats and mice. Inflammopharmacology. 19:255–263. 2011. View Article : Google Scholar : PubMed/NCBI
20	Wu YX, Wu TY, Xu BB, Xu XY, Chen HG, Li XY and Wang G: Protocatechuic acid inhibits osteoclast differentiation and stimulates apoptosis in mature osteoclasts. Biomed Pharmacother. 82:399–405. 2016. View Article : Google Scholar : PubMed/NCBI
21	Galois L, Etienne S, Grossin L, Watrin-Pinzano A, Cournil-Henrionnet C, Loeuille D, Netter P, Mainard D and Gillet P: Dose-response relationship for exercise on severity of experimental osteoarthritis in rats: A pilot study. Osteoarthritis Cartilage. 12:779–786. 2004. View Article : Google Scholar : PubMed/NCBI
22	Welberg LA, Kinkead B, Thrivikraman K, Huerkamp MJ, Nemeroff CB and Plotsky PM: Ketamine-xylazine-acepromazine anesthesia and postoperative recovery in rats. J Am Assoc Lab Anim Sci. 45:13–20. 2006.PubMed/NCBI
23	Nyska M, Amir H, Porath A and Dekel S: Radiological assessment of a modified anterior drawer test of the ankle. Foot Ankle. 13:400–403. 1992. View Article : Google Scholar : PubMed/NCBI
24	Nielsen RH, Stoop R, Leeming DJ, Stolina M, Qvist P, Christiansen C and Karsdal MA: Evaluation of cartilage damage by measuring collagen degradation products in joint extracts in a traumatic model of osteoarthritis. Biomarkers. 13:79–87. 2008. View Article : Google Scholar : PubMed/NCBI
25	Zhang Z, Wei X, Gao J, Zhao Y, Zhao Y, Guo L, Chen C, Duan Z, Li P and Wei L: Intra-Articular injection of cross-linked hyaluronic acid-dexamethasone hydrogel attenuates osteoarthritis: An experimental study in a rat model of osteoarthritis. Int J Mol Sci. 17:4112016. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Mau LP, Cheng WC, Chen JK, Shieh YS, Cochran DL and Huang RY: Curcumin ameliorates alveolar bone destruction of experimental periodontitis by modulating osteoclast differentiation, activation and function. J Funct Foods. 22:243–256. 2016. View Article : Google Scholar
28	Lu SH, Huang RY and Chou TC: Magnolol ameliorates ligature-induced periodontitis in rats and osteoclastogenesis: In vivo and in vitro study. Evid Based Complement Alternat Med. 2013:6340952013. View Article : Google Scholar : PubMed/NCBI
29	Woolf AD and Pfleger B: Burden of major musculoskeletal conditions. Bull World Health Organ. 81:646–656. 2003.PubMed/NCBI
30	Farkouh ME, Greenberg JD, Jeger RV, Ramanathan K, Verheugt FW, Chesebro JH, Kirshner H, Hochman JS, Lay CL, Ruland S, et al: Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis. 66:764–770. 2007. View Article : Google Scholar : PubMed/NCBI
31	Park SH, Kim JY, Cheon YH, Baek JM, Ahn SJ, Yoon KH, Lee MS and Oh J: Protocatechuic acid attenuates osteoclastogenesis by downregulating JNK/c-Fos/NFATc1 signaling and prevents inflammatory bone loss in mice. Phytother Res. 30:604–612. 2016. View Article : Google Scholar : PubMed/NCBI
32	Rousseau JC and Delmas PD: Biological markers in osteoarthritis. Nat Clin Pract Rheumatol. 3:346–356. 2007. View Article : Google Scholar : PubMed/NCBI
33	Garnero P, Rousseau JC and Delmas PD: Molecular basis and clinical use of biochemical markers of bone, cartilage, and synovium in joint diseases. Arthritis Rheum. 43:953–968. 2000. View Article : Google Scholar : PubMed/NCBI
34	Garnero P, Piperno M, Gineyts E, Christgau S, Delmas PD and Vignon E: Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: Relations with disease activity and joint damage. Ann Rheum Dis. 60:619–626. 2001. View Article : Google Scholar : PubMed/NCBI
35	Dong Z, Bonfil RD, Chinni S, Trindade Filho JC, Bhagat S, Bhagat S, Fridman R and Cher ML: Enhanced osteoclast motility due to overexpression of MMP-9 induced by prostate cancer cells. Cancer Res. 64:773. 2004.PubMed/NCBI
36	Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D and Galibert L: A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 390:175–179. 1997. View Article : Google Scholar : PubMed/NCBI
37	Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, et al: Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA. 96:3540–3545. 1999. View Article : Google Scholar : PubMed/NCBI
38	Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF and Siebenlist U: Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev. 11:3482–3496. 1997. View Article : Google Scholar : PubMed/NCBI
39	Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA and Wagner EF: C-Fos: A key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science. 266:443–448. 1994. View Article : Google Scholar : PubMed/NCBI
40	Lee ZH and Kim HH: Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Biophys Res Commun. 305:211–214. 2003. View Article : Google Scholar : PubMed/NCBI
41	Wong BR, Besser D, Kim N, Arron JR, Vologodskaia M, Hanafusa H and Choi Y: TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell. 4:1041–1049. 1999. View Article : Google Scholar : PubMed/NCBI
42	Kolbe L, Immeyer J, Batzer J, Wensorra U, tom Dieck K, Mundt C, Wolber R, Stäb F, Schönrock U, Ceilley RI and Wenck H: Anti-inflammatory efficacy of Licochalcone A: Correlation of clinical potency and in vitro effects. Arch Dermatol Res. 298:23–30. 2006. View Article : Google Scholar : PubMed/NCBI
43	Shui C, Riggs BL and Khosla S: The immunosuppressant rapamycin, alone or with transforming growth factor-beta, enhances osteoclast differentiation of RAW264.7 monocyte-macrophage cells in the presence of RANK-ligand. Calcif Tissue Int. 71:437–446. 2002. View Article : Google Scholar : PubMed/NCBI
44	Kim WS, Kim HJ, Lee ZH, Lee Y and Kim HH: Apolipoprotein E inhibits osteoclast differentiation via regulation of c-Fos, NFATc1 and NF-κB. Exp Cell Res. 319:436–446. 2013. View Article : Google Scholar : PubMed/NCBI
45	Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, Takeshita S, Wagner EF, Noda M, Matsuo K, et al: NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem. 282:18245–18253. 2007. View Article : Google Scholar : PubMed/NCBI
46	Takatsuna H, Asagiri M, Kubota T, Oka K, Osada T, Sugiyama C, Saito H, Aoki K, Ohya K, Takayanagi H and Umezawa K: Inhibition of RANKL-induced osteoclastogenesis by (−)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1. J Bone Miner Res. 20:653–662. 2005. View Article : Google Scholar : PubMed/NCBI
47	Luo L, Wei Q, Liu L, Lin X, Lin C, Zheng LI and Zhao J: Protocatechuic acid benefits proliferation and phenotypic maintenance of rabbit articular chondrocytes: An study. Exp Ther Med. 9:1865–1870. 2015. View Article : Google Scholar : PubMed/NCBI
48	Chin A, Yang Y, Chai L, Wong RW and Rabie AB: Effects of medicinal herb salvia miltiorrhiza on osteoblastic cells in vitro. J Orthop Res. 29:1059–1063. 2011. View Article : Google Scholar : PubMed/NCBI