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Leptin plays a catabolic role on articular cartilage

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Abstract

Leptin has been shown to play a crucial role in the regulation of body weight. There is also evidence that this adipokine plays a key role in the process of osteoarthritis. However, the precise role of leptin on articular cartilage metabolism is not clear. We investigate the role of leptin on articular cartilage in vivo in this study. Recombinant rat leptin (100 μg) was injected into the knee joints of rats, 48 h later, messenger RNA (mRNA) expression and protein levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), cathepsin D, and collagen II from articular cartilage were analyzed by real-time quantitative polymerase chain reaction (PCR) and western blot. Two important aggrecanases ADAMTS-4 and -5 (a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5) were also analyzed by real-time quantitative PCR. Besides, articular cartilage was also assessed for proteoglycan/GAG content by Safranin O staining. Leptin significantly increased both gene and protein levels of MMP-2, MMP-9, cathepsin D, and collagen II, while decreased bFGF markedly in cartilage. Moreover, the gene expression of ADAMTS-4 and -5 were markedly increased, and histologically assessed depletion of proteoglycan in articular cartilage was observed after treatment with leptin. These results strongly suggest that leptin plays a catabolic role on cartilage metabolism and may be a disadvantage factor involve in the pathological process of OA.

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References

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  CAS  PubMed  Google Scholar 

  2. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS (1998) Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 1:445–450

    Article  CAS  PubMed  Google Scholar 

  3. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E et al (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252

    Article  CAS  PubMed  Google Scholar 

  4. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS (2003) The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Investig 111:1409–1421

    CAS  PubMed  Google Scholar 

  5. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R et al (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271

    Article  CAS  PubMed  Google Scholar 

  6. Zarkesh-Esfahani H, Pockley G, Metcalfe RA, Bidlingmaier M, Wu Z, Ajami A et al (2001) High-dose leptin activates human leukocytes via receptor expression on monocytes. J Immunol 167:4593–4599

    CAS  PubMed  Google Scholar 

  7. Bjorbaek C, Uotani S, da Silva B, Flier JS (1997) Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 272:32686–32695

    Article  CAS  PubMed  Google Scholar 

  8. Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P et al (2003) Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 48:3118–3129

    Article  CAS  PubMed  Google Scholar 

  9. Kume K, Satomura K, Nishisho S, Kitaoka E, Yamanouchi K, Tobiume S et al (2002) Potential role of leptin in endochondral ossification. J Histochem Cytochem 50:159–169

    CAS  PubMed  Google Scholar 

  10. Otero M, Gomez Reino JJ, Gualillo O (2003) 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

    Article  CAS  PubMed  Google Scholar 

  11. Otero M, Lago R, Lago F, Reino JJ, Gualillo O (2005) 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

    Article  PubMed  Google Scholar 

  12. Simopoulou T, Malizos KN, Iliopoulos D, Stefanou N, Papatheodorou L, Ioannou M, Tsezou A (2007) Differential expression of leptin and leptin’s receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartil 15(8):872–883

    Article  CAS  Google Scholar 

  13. Busso N, So A, Chobaz-Peclat V, Morard C, Martinez-Soria E, Talabot-Ayer D et al (2002) Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J Immunol 168:875–882

    CAS  PubMed  Google Scholar 

  14. Lark MW, Bayne EK, Flanagan J, Harper CF, Hoerrner LA, Hutchinson NI et al (1997) Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. J Clin Investig 100:93–106

    Article  CAS  PubMed  Google Scholar 

  15. Poole AR (1999) An introduction to the pathophysiology of osteoarthritis. Front Biosci 4:D662–D670

    Article  CAS  PubMed  Google Scholar 

  16. Dean DD, Martel-Pelletier J, Pelletier JP, Howell DS, Woessner JF Jr (1989) Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. J Clin Investig 84:678–685

    Article  CAS  PubMed  Google Scholar 

  17. Tortorella MD, Malfait AM, Deccico C, Arner E (2001) The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in a model of cartilage degradation. Osteoarthritis Cartil 9:539–552

    Article  CAS  Google Scholar 

  18. Lang A, Horler D, Baici A (2000) The relative importance of cysteine peptidases in osteoarthritis. J Rheumatol 27:1970–1979

    CAS  PubMed  Google Scholar 

  19. Steppan CM, Crawford DT, Chidsey-Frink KL, Ke H, Swick AG (2000) Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 92:73–78

    Article  CAS  PubMed  Google Scholar 

  20. Bokarewa M, Bokarew D, Hultgren O, Tarkowski A (2003) Leptin consumption in the inflamed joints of patients with rheumatoid arthritis. Ann Rheum Dis 62:952–956

    Article  CAS  PubMed  Google Scholar 

  21. Ducy P, Schinke T, Karsenty G (2000) The osteoblast: a sophisticated fibroblast under central surveillance. Science 289:1501–1504

    Article  CAS  PubMed  Google Scholar 

  22. Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H et al (1996) The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci USA 93:8374–8378

    Article  CAS  PubMed  Google Scholar 

  23. Scharstuhl A, Glansbeek HL, van Beuningen HM, Vitters EL, van der Kraan PM, van den Berg WB (2002) Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J Immunol 169:507–514

    CAS  PubMed  Google Scholar 

  24. Grimaud E, Heymann D, Redini F (2002) Recent advances in TGF-beta effects on chondrocyte metabolism. Potential therapeutic roles of TGF-beta in cartilage disorders. Cytokine Growth Factor Rev 13:241–257

    Article  CAS  PubMed  Google Scholar 

  25. van Beuningen HM, Glansbeek HL, van der Kraan PM, van den Berg WB (2000) Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-beta injections. Osteoarthritis Cartil 8:25–33

    Article  Google Scholar 

  26. Hulth A, Johnell O, Miyazono K, Lindberg L, Heinegard D, Heldin CH (1996) Effect of transforming growth factor-beta and platelet-derived growth factor-BB on articular cartilage in rats. J Orthop Res 14:547–553

    Article  CAS  PubMed  Google Scholar 

  27. Woessner JF Jr (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5:2145–2154

    CAS  PubMed  Google Scholar 

  28. Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A et al (1993) Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4:197–250

    CAS  PubMed  Google Scholar 

  29. Kozaci LD, Buttle DJ, Hollander AP (1997) Degradation of type II collagen, but not proteoglycan, correlates with matrix metalloproteinase activity in cartilage explant cultures. Arthritis Rheum 40:164–174

    Article  CAS  PubMed  Google Scholar 

  30. Hsieh YS, Yang SF, Chu SC, Chen PN, Chou MC, Hsu MC et al (2004) Expression changes of gelatinases in human osteoarthritic knees and arthroscopic debridement. Arthroscopy 20:482–488

    Article  PubMed  Google Scholar 

  31. Ehrlich MG, Armstrong AL, Treadwell BV, Mankin HJ (1987) The role of proteases in the pathogenesis of osteoarthritis. J Rheumatol 14 Spec No:30–32

    Google Scholar 

  32. Murphy G, Cockett MI, Stephens PE, Smith BJ, Docherty AJ (1987) Stromelysin is an activator of procollagenase. A study with natural and recombinant enzymes. Biochem J 248:265–268

    CAS  PubMed  Google Scholar 

  33. Ellman MB, An HS, Muddasani P, Im HJ (2008) Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis. Gene 420:82–89

    Article  CAS  PubMed  Google Scholar 

  34. Loeser RF, Chubinskaya S, Pacione C, Im HJ (2005) Basic fibroblast growth factor inhibits the anabolic activity of insulin-like growth factor 1 and osteogenic protein 1 in adult human articular chondrocytes. Arthritis Rheum 52:3910–3917

    Article  CAS  PubMed  Google Scholar 

  35. Im HJ, Li X, Muddasani P, Kim GH, Davis F, Rangan J et al (2008) Basic fibroblast growth factor accelerates matrix degradation via a neuro-endocrine pathway in human adult articular chondrocytes. J Cell Physiol 215:452–463

    Article  CAS  PubMed  Google Scholar 

  36. Muddasani P, Norman JC, Ellman M, van Wijnen AJ, Im HJ (2007) Basic fibroblast growth factor activates the MAPK and NFkappaB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes. J Biol Chem 282:31409–31421

    Article  CAS  PubMed  Google Scholar 

  37. Kato Y, Iwamoto M, Koike T (1987) Fibroblast growth factor stimulates colony formation of differentiated chondrocytes in soft agar. J Cell Physiol 133:491–498

    Article  CAS  PubMed  Google Scholar 

  38. Fujimoto E, Ochi M, Kato Y, Mochizuki Y, Sumen Y, Ikuta Y (1999) Beneficial effect of basic fibroblast growth factor on the repair of full-thickness defects in rabbit articular cartilage. Arch Orthop Trauma Surg 119:139–145

    Article  CAS  PubMed  Google Scholar 

  39. Inoue A, Takahashi KA, Arai Y, Tonomura H, Sakao K, Saito M et al (2006) The therapeutic effects of basic fibroblast growth factor contained in gelatin hydrogel microspheres on experimental osteoarthritis in the rabbit knee. Arthritis Rheum 54:264–270

    Article  CAS  PubMed  Google Scholar 

  40. Yamamoto T, Wakitani S, Imoto K, Hattori T, Nakaya H, Saito M et al (2004) Fibroblast growth factor-2 promotes the repair of partial thickness defects of articular cartilage in immature rabbits but not in mature rabbits. Osteoarthritis Cartil 12:636–641

    Article  Google Scholar 

  41. Weisser J, Rahfoth B, Timmermann A, Aigner T, Brauer R, von der Mark K (2001) Role of growth factors in rabbit articular cartilage repair by chondrocytes in agarose. Osteoarthritis Cartil 9(Suppl A):S48–S54

    Article  Google Scholar 

  42. Klatt AR, Paul-Klausch B, Klinger G, Kuhn G, Renno JH, Banerjee M et al (2009) A critical role for collagen II in cartilage matrix degradation: collagen II induces pro-inflammatory cytokines and MMPs in primary human chondrocytes. J Orthop Res 27:65–70

    Article  CAS  PubMed  Google Scholar 

  43. Gordeladze JO, Drevon CA, Syversen U, Reseland JE (2002) Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: impact on differentiation markers, apoptosis, and osteoclastic signaling. J Cell Biochem 85:825–836

    Article  CAS  PubMed  Google Scholar 

  44. Enomoto H, Inoki I, Komiya K, Shiomi T, Ikeda E, Obata K et al (2003) Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am J Pathol 162:171–181

    CAS  PubMed  Google Scholar 

  45. Ballara S, Taylor PC, Reusch P, Marme D, Feldmann M, Maini RN et al (2001) Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum 44:2055–2064

    Article  CAS  PubMed  Google Scholar 

  46. Pfander D, Kortje D, Zimmermann R, Weseloh G, Kirsch T, Gesslein M et al (2001) Vascular endothelial growth factor in articular cartilage of healthy and osteoarthritic human knee joints. Ann Rheum Dis 60:1070–1073

    Article  CAS  PubMed  Google Scholar 

  47. Hashimoto S, Creighton-Achermann L, Takahashi K, Amiel D, Coutts RD, Lotz M (2002) Development and regulation of osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartil 10:180–187

    Article  CAS  Google Scholar 

  48. Pufe T, Petersen W, Tillmann B, Mentlein R (2001) The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum 44:1082–1088

    Article  CAS  PubMed  Google Scholar 

  49. Hardingham TE, Fosang AJ (1992) Proteoglycans: many forms and many functions. FASEB J 6:861–879

    CAS  PubMed  Google Scholar 

  50. Mankin HJ, Lippiello L (1970) Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. J Bone Joint Surg Am 52:424–434

    CAS  PubMed  Google Scholar 

  51. Palmoski M, Perricone E, Brandt KD (1979) Development and reversal of a proteoglycan aggregation defect in normal canine knee cartilage after immobilization. Arthritis Rheum 22:508–517

    Article  CAS  PubMed  Google Scholar 

  52. Moskowitz RW, Howell DS, Goldberg VM, Muniz O, Pita JC (1979) Cartilage proteoglycan alterations in an experimentally induced model of rabbit osteoarthritis. Arthritis Rheum 22:155–163

    Article  CAS  PubMed  Google Scholar 

  53. Dunham J, Chambers MG, Jasani MK, Bitensky L, Chayen J (1989) Quantitative criteria for evaluating the early development of osteoarthritis and the effect of diclofenac sodium. Agents Actions 28:93–97

    Article  CAS  PubMed  Google Scholar 

  54. Sztrolovics R, Alini M, Roughley PJ, Mort JS (1997) Aggrecan degradation in human intervertebral disc and articular cartilage. Biochem J 326:235–241

    CAS  PubMed  Google Scholar 

  55. Fosang AJ, Neame PJ, Last K, Hardingham TE, Murphy G, Hamilton JA (1992) The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. J Biol Chem 267:19470–19474

    CAS  PubMed  Google Scholar 

  56. Ilic MZ, Handley CJ, Robinson HC, Mok MT (1992) Mechanism of catabolism of aggrecan by articular cartilage. Arch Biochem Biophys 294:115–122

    Article  CAS  PubMed  Google Scholar 

  57. Tortorella MD, Burn TC, Pratta MA, Abbaszade I, Hollis JM, Liu R et al (1999) Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. Science 284:1664–1666

    Article  CAS  PubMed  Google Scholar 

  58. Collins-Racie LA, Flannery CR, Zeng W, Corcoran C, Annis-Freeman B, Agostino MJ et al (2004) ADAMTS-8 exhibits aggrecanase activity and is expressed in human articular cartilage. Matrix Biol 23:219–230

    Article  CAS  PubMed  Google Scholar 

  59. Patel KP, Sandy JD, Akeda K, Miyamoto K, Chujo T, An HS et al (2007) Aggrecanases and aggrecanase-generated frag-ments in the human intervertebral disc at early and advanced stages of disc degeneration. Spine 32:2596–2603

    Article  PubMed  Google Scholar 

  60. Zeng W, Corcoran C, Collins-Racie LA, Lavallie ER, Morris EA, Flannery CR (2006) Glycosaminoglycan-binding properties and aggrecanase activities of truncated ADAMTSs: comparative analyses with ADAMTS-5, -9, -16 and -18. Biochim Biophys Acta 1760:517–524

    CAS  PubMed  Google Scholar 

  61. Fushimi K, Troeberg L, Nakamura H, Lim NH, Nagase H (2008) Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activity. J Biol Chem 283:6706–6716

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Jun Liu and Wei-guo Yang for providing excellent technical assistance. This work was supported by the Health Bureau of Zhejiang Province (2006A055).

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  1. Department of Orthopedics Surgery, The Second Hospital of Medical College, Zhejiang University College of Medicine, JieFang Road 88#, 310009, Hangzhou, People’s Republic of China

    Jia-peng Bao, Wei-ping Chen, Jie Feng, Peng-fei Hu, Zhong-li Shi & Li-dong Wu

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  1. Jia-peng Bao
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Correspondence to Li-dong Wu.

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Bao, Jp., Chen, Wp., Feng, J. et al. Leptin plays a catabolic role on articular cartilage. Mol Biol Rep 37, 3265–3272 (2010). https://doi.org/10.1007/s11033-009-9911-x

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