P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritisReportar como inadecuado




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Journal of Inflammation

, 5:22

First Online: 04 December 2008Received: 12 February 2008Accepted: 04 December 2008

Abstract

BackgroundEvaluate the potential role of p38 inhibitors for the treatment of osteoarthritis using an animal model of joint degeneration iodoacetate-induced arthritis and a pain model Hargraeves assay.

MethodsP38 kinase activity was evaluated in a kinase assay by measuring the amount of phosphorylated substrate ATF2 using a phosphoATF2 Thr specific primary antibody and an alkaline phosphate coupled secondary antibody and measuring the OD at 405 nm. TNFα and IL-1β secretion from LPS stimulated THP-1 monocytic cells and human peripheral blood mononuclear cells were measured by ELISA. Rats treated with vehicle or p38 inhibitor were injected intra-articularly in one knee with iodoacetate and damage to the tibial plateau was assessed from digitized images captured using an image analyzer. The effect of p38 inhibitors on hyperalgesia was evaluated in rats given an intraplantar injection of carrageenan and 4 h later the paw withdrawal time to a radiant heat source was measured.

ResultsSB-203580 and VX-745 are both potent inhibitors of p38 with IC50s of 136 ± 64 nM and 35 ± 14 nM mean ± S.D., respectively. Similarly, SB-203580 and VX-745 potently inhibited TNF release from LPS stimulated human THP-1 cells with IC50s of 72 ± 15 nM; and 29 ± 14 nM mean ± S.D. respectively. TNF release from LPS stimulated human peripheral blood mononuclear cells was inhibited with IC50s 16 ± 6 nM and 14 ± 8 nM, mean ± S.D. for SB-203580 and VX-745 and IL-1 was inhibited with IC50s of 20 ± 8 nM and 15 ± 4 nM mean ± S.D., respectively. SB-203580 and VX-745 administered orally at a dose of 50 mg-kg resulted in the significant p < 0.05 inhibition of joint degeneration in the rat iodoacetate model of 45% and 31%, respectively. SB-203580 demonstrated a dose related inhibition of joint degeneration of 30, 25, 12 and 8% at 50, 25, 10 and 5 mg-kg p.o. b.i.d. in the rat iodoacetate model. Similarly, both p38 inhibitors significantly p < 0.05 attenuated the pain response paw withdrawal time in the Hargraeves hyperalgesia assay when administered orally at 30, 10 and 3 mg-kg.

ConclusionSB203580 and VX-745 demonstrated attenuation of both cartilage degeneration and pain in animal models and suggest that p38 inhibitors may be a useful approach for the treatment of osteoarthritis.

AbbreviationsTNFαTumor necrosis factor alpha

IL-1αinterleukin 1 α

OAosteoarthritis

p38p38 mitogen activated kinase

PBMCsperipheral blood mononuclear cells.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-9255-5-22 contains supplementary material, which is available to authorized users.

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Autor: Kimberly K Brown - Sandra A Heitmeyer - Erin B Hookfin - Lily Hsieh - Maria Buchalova - Yetunde O Taiwo - Michael J Ja

Fuente: https://link.springer.com/







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