Function of sustained released resveratrol on IL-1 β -induced hBMSC MMP13 secretion inhibition and chondrogenic differentiation promotion

Abstract

Metalloproteinase-13 is the major type II collagenase that directly implicates cartilage matrix destruction. Metalloproteinase-13 is inducted and activated by interleukin-1β, which is a commonly observed proinflammatory cytokine in the joint cavity of arthritic patients. Depression of interleukin-1β function can inhibit metalloproteinase-13 expression and protect the cartilage extracellular matrix. In this study, resveratrol release microspheres were developed, and the direct function of the released resveratrol on the interleukin-1β was discussed. The resveratrol-loaded microspheres were fabricated using oil-in-water emulsion and solution-evaporation methods. The particle size and the encapsulation efficiency for the techniques, which used different fabrication conditions, were within 8.3–63.9 μm and 37%–82%, respectively. The effect of drug release lasted for more than 650 h in a PBS solution at 37℃. Human bone mesenchymal stem cells were chosen for cell experiments. Interleukin-1β was used to induce an inflammatory condition. The effect of sustained resveratrol release from the microspheres on the cells' gene expression was observed using the transwell co-culturing method. The results indicated that metalloproteinase-13 mRNA expression was upregulated after interleukin-1β induction. The released resveratrol directly inhibited the function of interleukin-1β and thus downregulated metalloproteinase-13 mRNA expression. Moreover, the upregulation of Col2, aggrecan and Sox9 mRNA expressions, which are major chondrocyte markers, was observed after resveratrol was released into the culture medium. Resveratrol was observed to maintain the cells' chondrogenic gene expression when subject to the inflammation condition. The sustained released resveratrol inhibited interleukin-1β-inducted metalloproteinase-13 activation and promoted chondrocyte differentiation. This drug-loading microsphere is a promising candidate for arthritis therapy.

Keywords

Resveratrol microsphere human bone mesenchymal stem cells metalloproteinase-13 sustained-release

Get full access to this article

View all access options for this article.

References

Makris

Gomoll

Malizos

. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol 2015; 11: 21–34.

Fernandes

Martel-Pelletier

Pelletier

. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002; 39: 237–246. .

Madeira

Santhagunam

Salgueiro

. Advanced cell therapies for articular cartilage regeneration. Trends in biotechnology 2015; 33: 35–42.

Christine

Han

Lawrence

. Detection of interleukin-1 in the cartilage of patients with osteoarthritis: a possible autocrine/paracrine role in pathogenesis. Osteoarthritis Cartil 1997; 5: 293–300.

Stern

Carvalho

Buck

. Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta. Osteoarthritis Cartil 2003; 11: 394–402.

Daheshia

Yao

. The interleukin 1β pathway in the pathogenesis of osteoarthritis. J Rheumatol 2008; 35: 2306–2312.

Fernandes

Martel-Pelletier

Pelletier

J-P

. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002; 39: 237–246.

Csaki

Mobasheri

Shakibaei

. Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1β-induced NF-κB-mediated inflammation and apoptosis. Arthritis Res Ther 2009, pp. 11.

Abdelhamid

Judith

Wen

. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol 2002; 21: 251–262.

10.

Bhardwaj

Sethi

Vadhan-Raj

. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-κB–regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 2007; 109: 2293–2302.

11.

Estrov

Shishodia

Faderl

. Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. Blood 2003; 102: 987–995.

12.

Kim

Lim

S-Y

Rhee

S-H

. Resveratrol inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in β-amyloid-treated C6 glioma cells. Int J Molecul Med 2006; 17: 1069–1075.

13.

Yar

Menevse

Alp

. The effects of resveratrol on cyclooxygenase-1 and cyclooxygenase-2 mRNA and protein levels in diabetic rat kidneys. Mol Biol Rep 2010; 37: 2323–2331.

14.

Elmali

Baysal

Harma

. Effects of resveratrol in inflammatory arthritis. Inflammation 2007; 30: 1–6.

15.

Amri

Chaumeil

Sfar

. Administration of resveratrol: What formulation solutions to bioavailability limitations? J Control Release 2012; 158: 182–193.

16.

Shi

Rao

. Stabilization and encapsulation of photosensitive resveratrol within yeast cell. Int J Pharmaceut 2008; 349: 83–93.

17.

Das

K-Y

. Colon-specific delivery of resveratrol: optimization of multi-particulate calcium-pectinate carrier. Int J Pharmaceut 2010; 385: 20–28.

18.

Peng

Xiong

. Vanillin cross-linked chitosan microspheres for controlled release of resveratrol. Food Chem 2010; 121: 23–28.

19.

Cheng

. Complexation of resveratrol with cyclodextrins: solubility and antioxidant activity. Food Chem 2009; 113: 17–20.

20.

Teskač

Kristl

. The evidence for solid lipid nanoparticles mediated cell uptake of resveratrol. Int J Pharmaceut 2010; 390: 61–69.

21.

Kristl

Teskač

Caddeo

. Improvements of cellular stress response on resveratrol in liposomes. Eur J Pharmaceut Biopharmaceut 2009; 73: 253–259.

22.

Amri

Chaumeil

Sfar

. Administration of resveratrol: what formulation solutions to bioavailability limitations? J Control Release 2012; 158: 182–193.

23.

Wang

. Local delivery system using thermosensitive hydrogel and drug loading microspheres for cartilage repairing. Adv Mater Res 2014; 898: 300–303.

24.

O'Donnell

McGinity

. Preparation of microspheres by the solvent evaporation technique. Adv Drug Delivery Rev 1997; 28: 25–42.

25.

Mengshol

Vincenti

Coon

. Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-jun N-terminal kinase, and nuclear factor κB: differential regulation of collagenase 1 and collagenase 3. Arthritis Rheumat 2000; 43: 801–11.

26.

Wischke

Schwendeman

. Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles. Int J Pharmaceut 2008; 364: 298–327.

27.

Ping

Gao

. Effects of formulation factors on encapsulation efficiency and release behaviour in vitro of huperzine A-PLGA microspheres. J Microencapsulation 2005; 22: 705–714.

28.

Miagkov

Kovalenko

Brown

. NF-κB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Nat Acad Sci 1998; 95: 13859–13864.

29.

Deng

Zhang

. Sox9 is required for cartilage formation. Nat Genet 1999; 22: 85–89.

30.

Dudhia

. Aggrecan, aging and assembly in articular cartilage. Cell Mol Life Sci 2005; 62: 2241–2256.

31.

Kim

Braun

Dragoo

. The effect of resveratrol on normal and osteoarthritic chondrocyte metabolism. Bone Joint Res 2014; 3: 51–59.

32.

Dvir-Ginzberg

Gagarina

Lee

. Regulation of cartilage-specific gene expression in human chondrocytes by SirT1 and nicotinamide phosphoribosyltransferase. J Biol Chem 2008; 283: 36300–36310.