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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Satyanarayana Medicherla, Jing Ying Ma, Ruban Mangadu, Yebin Jiang, Jenny J. Zhao, Ramona Almirez, Irene Kerr, Elizabeth G. Stebbins, Gilbert O'Young, Ann M. Kapoun, Gregory Luedtke, Sarvajit Chakravarty, Sundeep Dugar, Harry K. Genant and Andrew A. Protter
Journal of Pharmacology and Experimental Therapeutics July 2006, 318 (1) 132-141; DOI: https://doi.org/10.1124/jpet.105.098020
Satyanarayana Medicherla
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Jing Ying Ma
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Ruban Mangadu
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Yebin Jiang
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Jenny J. Zhao
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Ramona Almirez
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Irene Kerr
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Elizabeth G. Stebbins
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Gilbert O'Young
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Ann M. Kapoun
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Gregory Luedtke
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Sarvajit Chakravarty
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Sundeep Dugar
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Harry K. Genant
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Abstract

Destruction of cartilage and bone is a poorly managed hallmark of human rheumatoid arthritis (RA). p38 Mitogen-activated protein kinase (MAPK) has been shown to regulate key proinflammatory pathways in RA, including tumor necrosis factor α, interleukin (IL)-1β, and cyclooxygenase-2, as well as the process of osteoclast differentiation. Therefore, we evaluated whether a p38α MAPK inhibitor, indole-5-carboxamide (SD-282), could modulate cartilage and bone destruction in a mouse model of RA induced with bovine type II collagen [collagen-induced arthritis (CIA)]. In mice with early disease, SD-282 treatment significantly improved clinical severity scores, reduced bone and cartilage loss, and reduced mRNA levels of proinflammatory genes in paw tissue, including IL-1β, IL-6, and cyclooxygenase-2. Notably, SD-282 treatment of mice with advanced disease resulted in significant improvement in clinical severity scoring and paw swelling, a reversal in bone and cartilage destruction as assessed by histology, bone volume fraction and thickness, and three-dimensional image analysis. These changes were accompanied by reduced osteoclast number and lowered levels of serum cartilage oligomeric matrix protein, a marker of cartilage breakdown. Thus, in a model of experimental arthritis associated with significant osteolysis, p38α MAPK inhibition not only attenuates disease progression but also reverses cartilage and bone destruction in mice with advanced CIA disease.

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  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.105.098020.

  • ABBREVIATIONS: RA, rheumatoid arthritis; TNF, tumor necrosis factor; IL, interleukin; COX, cyclooxygenase; MAPK, mitogen-activated protein kinase; SD-282, indole-5-carboxamide (ATP-competitive inhibitor of p38 kinase), CIA, collagen-induced arthritis; PGE2, prostaglandin E2; FR167653, pyridinyl imidazole compound (specific inhibitor of p38 pathway); LPS, lipopolysaccharide; ELISA, enzyme-linked immunosorbent assay; SB202190, (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole; COMP, cartilage oligomeric matrix protein; 3-D, three-dimensional; micro-CT, μCT, microcomputed tomography.

    • Received November 2, 2005.
    • Accepted March 24, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 3
1 Jun 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Satyanarayana Medicherla, Jing Ying Ma, Ruban Mangadu, Yebin Jiang, Jenny J. Zhao, Ramona Almirez, Irene Kerr, Elizabeth G. Stebbins, Gilbert O'Young, Ann M. Kapoun, Gregory Luedtke, Sarvajit Chakravarty, Sundeep Dugar, Harry K. Genant and Andrew A. Protter
Journal of Pharmacology and Experimental Therapeutics July 1, 2006, 318 (1) 132-141; DOI: https://doi.org/10.1124/jpet.105.098020

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Satyanarayana Medicherla, Jing Ying Ma, Ruban Mangadu, Yebin Jiang, Jenny J. Zhao, Ramona Almirez, Irene Kerr, Elizabeth G. Stebbins, Gilbert O'Young, Ann M. Kapoun, Gregory Luedtke, Sarvajit Chakravarty, Sundeep Dugar, Harry K. Genant and Andrew A. Protter
Journal of Pharmacology and Experimental Therapeutics July 1, 2006, 318 (1) 132-141; DOI: https://doi.org/10.1124/jpet.105.098020
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