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Differential effects of SB 242235, a selective p38 mitogen-activated protein kinase inhibitor, on IL-1 treated bovine and human cartilage/chondrocyte cultures.
Osteoarthritis Cartilage. 2000 Nov; 8(6):434-43.OC

Abstract

The p38 MAP kinase inhibitor, SB 242235, was evaluated for its effects on the metabolism of bovine and human cartilage and primary chondrocyte cultures. SB 242235 had no effect on proteoglycan synthesis (PG) in bovine articular cartilage explants (BAC), as measured by [(35)S]-sulfate incorporation into glycosaminoglycans (GAGs). In addition, the compound had no effect on IL-1 alpha-induced GAG release from these cultures. However, there was a potent, dose-dependent inhibition of nitric oxide (NO) release from IL-1 alpha-stimulated BAC with an IC(50)of approximately 0.6 microM, with similar effects observed in primary chondrocytes. The effect on BAC was time dependent, and mechanistically did not appear to be the result of inhibition of protein kinase C (PKC), protein kinase A (PKA) or MEK-1. The effect on NO release in bovine chondrocytes was at the level of inducible nitric oxide synthase (iNOS) gene expression, which was inhibited at similar concentrations as nitrite production. In primary human chondrocytes, IL-1 beta induction of p38 MAP kinase was inhibited by SB 242235 with an IC(50)of approximately 1 microM. Surprisingly, however, treatment of IL-beta-stimulated human cartilage or chondrocytes with SB 242235 did not inhibit either NO production or the induction of iNOS. On the other hand, the natural product hymenialdisine (HYM), a protein tyrosine kinase (PTK) inhibitor, inhibited NO production and iNOS in both species. In contrast to the differential control of iNOS, PGE(2)was inhibited by SB 242235 in both IL-1-stimulated bovine and human chondrocyte cultures. These studies indicate that there are species differences in the control of iNOS by p38 inhibitors and also that different pathways may control IL-1-induced proteoglycan breakdown and NO production.

Authors+Show Affiliations

Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Alison_M_Badger@SBPHRD.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11069728

Citation

Badger, A M., et al. "Differential Effects of SB 242235, a Selective P38 Mitogen-activated Protein Kinase Inhibitor, On IL-1 Treated Bovine and Human Cartilage/chondrocyte Cultures." Osteoarthritis and Cartilage, vol. 8, no. 6, 2000, pp. 434-43.
Badger AM, Roshak AK, Cook MN, et al. Differential effects of SB 242235, a selective p38 mitogen-activated protein kinase inhibitor, on IL-1 treated bovine and human cartilage/chondrocyte cultures. Osteoarthr Cartil. 2000;8(6):434-43.
Badger, A. M., Roshak, A. K., Cook, M. N., Newman-Tarr, T. M., Swift, B. A., Carlson, K., Connor, J. R., Lee, J. C., Gowen, M., Lark, M. W., & Kumar, S. (2000). Differential effects of SB 242235, a selective p38 mitogen-activated protein kinase inhibitor, on IL-1 treated bovine and human cartilage/chondrocyte cultures. Osteoarthritis and Cartilage, 8(6), 434-43.
Badger AM, et al. Differential Effects of SB 242235, a Selective P38 Mitogen-activated Protein Kinase Inhibitor, On IL-1 Treated Bovine and Human Cartilage/chondrocyte Cultures. Osteoarthr Cartil. 2000;8(6):434-43. PubMed PMID: 11069728.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of SB 242235, a selective p38 mitogen-activated protein kinase inhibitor, on IL-1 treated bovine and human cartilage/chondrocyte cultures. AU - Badger,A M, AU - Roshak,A K, AU - Cook,M N, AU - Newman-Tarr,T M, AU - Swift,B A, AU - Carlson,K, AU - Connor,J R, AU - Lee,J C, AU - Gowen,M, AU - Lark,M W, AU - Kumar,S, PY - 2000/11/9/pubmed PY - 2001/3/3/medline PY - 2000/11/9/entrez SP - 434 EP - 43 JF - Osteoarthritis and cartilage JO - Osteoarthr. Cartil. VL - 8 IS - 6 N2 - The p38 MAP kinase inhibitor, SB 242235, was evaluated for its effects on the metabolism of bovine and human cartilage and primary chondrocyte cultures. SB 242235 had no effect on proteoglycan synthesis (PG) in bovine articular cartilage explants (BAC), as measured by [(35)S]-sulfate incorporation into glycosaminoglycans (GAGs). In addition, the compound had no effect on IL-1 alpha-induced GAG release from these cultures. However, there was a potent, dose-dependent inhibition of nitric oxide (NO) release from IL-1 alpha-stimulated BAC with an IC(50)of approximately 0.6 microM, with similar effects observed in primary chondrocytes. The effect on BAC was time dependent, and mechanistically did not appear to be the result of inhibition of protein kinase C (PKC), protein kinase A (PKA) or MEK-1. The effect on NO release in bovine chondrocytes was at the level of inducible nitric oxide synthase (iNOS) gene expression, which was inhibited at similar concentrations as nitrite production. In primary human chondrocytes, IL-1 beta induction of p38 MAP kinase was inhibited by SB 242235 with an IC(50)of approximately 1 microM. Surprisingly, however, treatment of IL-beta-stimulated human cartilage or chondrocytes with SB 242235 did not inhibit either NO production or the induction of iNOS. On the other hand, the natural product hymenialdisine (HYM), a protein tyrosine kinase (PTK) inhibitor, inhibited NO production and iNOS in both species. In contrast to the differential control of iNOS, PGE(2)was inhibited by SB 242235 in both IL-1-stimulated bovine and human chondrocyte cultures. These studies indicate that there are species differences in the control of iNOS by p38 inhibitors and also that different pathways may control IL-1-induced proteoglycan breakdown and NO production. SN - 1063-4584 UR - https://www.unboundmedicine.com/medline/citation/11069728/Differential_effects_of_SB_242235_a_selective_p38_mitogen_activated_protein_kinase_inhibitor_on_IL_1_treated_bovine_and_human_cartilage/chondrocyte_cultures_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1063-4584(99)90319-9 DB - PRIME DP - Unbound Medicine ER -