Leptin induces the apoptosis of chondrocytes in an in vitro model of osteoarthritis via the JAK2‑STAT3 signaling pathway

Zhang,Zi Ming; Shen,Chao; Li,Hai; Fan,Qing; Ding,Jing; Jin,Fang Chun; Sha,Lin

doi:10.3892/mmr.2016.4970

Leptin induces the apoptosis of chondrocytes in an in vitro model of osteoarthritis via the JAK2‑STAT3 signaling pathway

Authors:
- Zi Ming Zhang
- Chao Shen
- Hai Li
- Qing Fan
- Jing Ding
- Fang Chun Jin
- Lin Sha
View Affiliations

Affiliations: Department of Pediatric Orthopedics, Xin Hua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200092, P.R. China, Department of Orthopedics, Xin Hua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200092, P.R. China
Published online on: March 3, 2016 https://doi.org/10.3892/mmr.2016.4970
Pages: 3684-3690

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Emerging data has suggested a high prevalence of osteoarthritis (OA) among obese people. As an important adipokine secreted by white adipose tissue, leptin may be a key mediator in the progression of OA. Leptin exerts a catabolic effect on OA cartilage by increasing the production of metalloproteinase (MMP) enzymes, and contributes to apoptosis in chondrocytes. The current study aimed to explore the role of leptin on the apoptosis of chondrocytes in OA, and its underlying mechanisms. In the in vitro model of OA used in the present study, administration of exogenous leptin induced the generation of reactive oxygen species (ROS) and apoptosis in chondrocytes. It has been demonstrated that leptin is associated with the pathogenesis of OA via the Janus kinase 2 (JAK2)‑signal transducer and activator of transcription 3 (STAT3) signaling pathway, and data gathered in the present study demonstrated that suppression of this signaling pathway using a JAK2 inhibitor, AG490, significantly ameliorated leptin‑induced apoptosis in damaged chondrocytes in vitro, and reduced the generation of ROS. Furthermore, the protein expression levels of MMP‑13 and B‑cell lymphoma 2‑associated X protein were downregulated in the AG490‑treated group. The results of the present study may provide insight into the underlying molecular mechanism by which leptin induces apoptosis in chondrocytes. These findings indicated the importance of leptin as a therapeutic target for the treatment of OA in the overweight population.

View Figures

View References

1	Felson DT: An update on the pathogenesis and epidemiology of osteoarthritis. Radiol Clin North Am. 42:1–9. 2004. View Article : Google Scholar : PubMed/NCBI
2	Gregor MF and Hotamisligil GS: Inflammatory mechanisms in obesity. Annu Rev Immunol. 29:415–445. 2011. View Article : Google Scholar : PubMed/NCBI
3	Yusuf E, Nelissen RG, Ioan-Facsinay A, Stojanovic-Susulic V, DeGroot J, van Osch G, Middeldorp S, Huizinga TW and Kloppenburg M: Association between weight or body mass index and hand osteoarthritis: A systematic review. Ann Rheum Dis. 69:761–765. 2010. View Article : Google Scholar
4	Pottie P, Presle N, Terlain B, Netter P, Mainard D and Berenbaum F: Obesity and osteoarthritis: More complex than predicted! Ann Rheum Dis. 65:1403–1405. 2006. View Article : Google Scholar : PubMed/NCBI
5	Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P and Pottie P: Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum. 48:3118–3129. 2003. View Article : Google Scholar : PubMed/NCBI
6	Figenschau Y, Knutsen G, Shahazeydi S, Johansen O and Svein-björnsson B: Human articular chondrocytes express functional leptin receptors. Biochem Biophys Res Commun. 287:190–197. 2001. View Article : Google Scholar : PubMed/NCBI
7	Vuolteenaho K, Koskinen A, Kukkonen M, Nieminen R, Päivärinta U, Moilanen T and Moilanen E: Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage-mediator role of NO in leptin-induced PGE2, IL-6 and IL-8 production. Mediators Inflamm. 2009:3458382009. View Article : Google Scholar
8	Li D, Xie G and Wang W: Reactive oxygen species: The 2-edged sword of osteoarthritis. Am J Med Sci. 344:486–490. 2012. View Article : Google Scholar : PubMed/NCBI
9	Otero M, Lago R, Lago F, Reino JJ and Gualillo O: Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: Synergistic effect of leptin with interleukin-1. Arthritis Res Ther. 7:R581–R591. 2005. View Article : Google Scholar : PubMed/NCBI
10	Koskinen A, Vuolteenaho K, Nieminen R, Moilanen T and Moilanen E: Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients. Clin Exp Rheumatol. 29:57–64. 2011.PubMed/NCBI
11	Otero M, Gomez Reino JJ and Gualillo O: Synergistic induction of nitric oxide synthase type II: In vitro effect of leptin and interferon-gamma in human chondrocytes and ATDC5 chondrogenic cells. Arthritis Rheum. 48:404–409. 2003. View Article : Google Scholar : PubMed/NCBI
12	Pickarski M, Hayami T, Zhuo Y and Duong LT: Molecular changes in articular cartilage and subchondral bone in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. BMC Musculoskelet Disord. 12:1972011. View Article : Google Scholar : PubMed/NCBI
13	Tew SR, Murdoch AD, Rauchenberg RP and Hardingham TE: Cellular methods in cartilage research: Primary human chondrocytes in culture and chondrogenesis in human bone marrow stem cells. Methods. 45:2–9. 2008. View Article : Google Scholar : PubMed/NCBI
14	Hamada Y, Fujii H and Fukagawa M: Role of oxidative stress in diabetic bone disorder. Bone. 45(Suppl 1): S35–S38. 2009. View Article : Google Scholar : PubMed/NCBI
15	Ghilardi N and Skoda RC: The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol Endocrinol. 11:393–399. 1997. View Article : Google Scholar : PubMed/NCBI
16	Ohba S, Lanigan TM and Roessler BJ: Leptin receptor JAK2/STAT3 signaling modulates expression of Frizzled receptors in articular chondrocytes. Osteoarthritis Cartilage. 18:1620–1629. 2010. View Article : Google Scholar : PubMed/NCBI
17	Mutabaruka MS, Aoulad Aissa M, Delalandre A, Lavigne M and Lajeunesse D: Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression. Arthritis Res Ther. 12:R202010. View Article : Google Scholar : PubMed/NCBI
18	Bahrenberg G, Behrmann I, Barthel A, Hekerman P, Heinrich PC, Joost HG and Becker W: Identification of the critical sequence elements in the cytoplasmic domain of leptin receptor isoforms required for Janus kinase/signal transducer and activator of transcription activation by receptor heterodimers. Mol Endocrinol. 16:859–872. 2002. View Article : Google Scholar : PubMed/NCBI
19	Adams JM and Cory S: Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci. 26:61–66. 2001. View Article : Google Scholar : PubMed/NCBI
20	Lotz MK and Caramés B: Autophagy and cartilage homeostasis mechanisms in joint health, aging and osteoarthritis. Nat Rev Rheumatol. 7:579–587. 2011.PubMed/NCBI
21	Shapiro IM, Layfield R, Lotz M, Settembre C and Whitehouse C: Boning up on autophagy: The role of autophagy in skeletal biology. Autophagy. 10:7–19. 2014. View Article : Google Scholar :
22	Aspden RM: Obesity punches above its weight in osteoarthritis. Nat Rev Rheumatol. 7:65–68. 2011. View Article : Google Scholar
23	Friedman JM and Halaas JL: Leptin and the regulation of body weight in mammals. Nature. 395:763–770. 1998. View Article : Google Scholar : PubMed/NCBI
24	Gualillo O, Eiras S, Lago F, Diéguez C and Casanueva FF: Elevated serum leptin concentrations induced by experimental acute inflammation. Life Sci. 67:2433–2441. 2000. View Article : Google Scholar : PubMed/NCBI
25	Presle N, Pottie P, Dumond H, Guillaume C, Lapicque F, Pallu S, Mainard D, Netter P and Terlain B: Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis Cartilage. 14:690–695. 2006. View Article : Google Scholar : PubMed/NCBI
26	Distel E, Cadoudal T, Durant S, Poignard A, Chevalier X and Benelli C: The infrapatellar fat pad in knee osteoarthritis: An important source of interleukin-6 and its soluble receptor. Arthritis Rheum. 60:3374–3377. 2009. View Article : Google Scholar : PubMed/NCBI
27	Goldring MB, Tsuchimochi K and Ijiri K: The control of chondrogenesis. J Cell Biochem. 97:33–44. 2006. View Article : Google Scholar
28	Hashimoto S, Takahashi K, Amiel D, Coutts RD and Lotz M: Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis. Arthritis Rheum. 41:1266–1274. 1998. View Article : Google Scholar : PubMed/NCBI
29	Henrotin Y and Kurz B: Antioxidant to treat osteoarthritis: Dream or reality? Curr Drug Targets. 8:347–357. 2007. View Article : Google Scholar : PubMed/NCBI
30	Almonte-Becerril M, Navarro-Garcia F, Gonzalez-Robles A, Vega-Lopez MA, Lavalle C and Kouri JB: Cell death of chondrocytes is a combination between apoptosis and autophagy during the pathogenesis of Osteoarthritis within an experimental model. Apoptosis. 15:631–638. 2010. View Article : Google Scholar : PubMed/NCBI