Abstract:
BACKGROUND:As an initial step in the development of a local therapeutic to treat osteoarthritis (OA), a number of agents were tested for their ability to block activation of inflammation through nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), subchondral bone changes through receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclastogenesis, and proteolytic degradation through matrix metalloproteinase (MMP)-13 activity. Candidates with low toxicity and predicted efficacy were further examined using either of two widely accepted models of OA joint degeneration in the rat: the monoiodoacetic acid (MIA) model or the medial meniscal tear/medial collateral ligament tear (MMT/MCLT) model. METHODS:Potential therapeutics were assessed for their effects on the activation of nuclear factor (NF)-κB, RANKL-mediated osteoclastogenesis, and MMP-13 activity in vitro using previously established assays. Toxicity was measured using HeLa cells, a synovial cell line, or primary human chondrocytes. Drugs predicted to perform well in vivo were tested either systemically or via intraarticular injection in the MIA or the MMT/MCLT model of OA. Pain behavior was measured by mechanical hyperalgesia using the digital Randall-Selitto test (dRS) or by incapacitance with weight bearing (WB). Joint degeneration was evaluated using micro computed tomography and a comprehensive semiquantitative scoring of cartilage, subchondral bone, and synovial histopathology. RESULTS:Several agents were effective both in vitro and in vivo. With regard to pain behavior, systemically delivered clonidine was superior in treating MIA-induced changes in WB or dRS, while systemic clonidine, curcumin, tacrolimus, and fluocinolone were all somewhat effective in modifying MMT/MCLT-induced changes in WB. Systemic tacrolimus was the most effective in slowing disease progression as measured by histopathology in the MMT/MCLT model. CONCLUSIONS:All of the agents that demonstrated highest benefit in vivo, excepting clonidine, were found to inhibit MMP-13, NF-κB, and bone matrix remodeling in vitro. The MIA and MMT/MCLT models of OA, previously shown to possess inflammatory characteristics and to display associated pain behavior, were affected to different degrees by the same drugs. Although no therapeutic was remarkable across all measures, the several which showed the most promise in either model merit continued study with alternative dosing and therapeutic strategies.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
TenBroek EM,Yunker L,Nies MF,Bendele AMdoi
10.1186/s13075-016-0921-5subject
Has Abstractpub_date
2016-01-21 00:00:00pages
24eissn
1478-6354issn
1478-6362pii
10.1186/s13075-016-0921-5journal_volume
18pub_type
杂志文章abstract:INTRODUCTION:Though remission is currently a treatment goal in patients with rheumatoid arthritis (RA), the number of patients who achieve and sustain remission in daily practice is still small. It is suggested that early remission will be associated with sustainability of remission. The aim was to study the associatio...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3027
更新日期:2010-01-01 00:00:00
abstract::Anti-Sa antibodies are detected in the serum of 20-47% of patients with rheumatoid arthritis. These antibodies have a high degree of specificity for the disease, and appear to identify a subset of early rheumatoid arthritis patients destined to have aggressive and destructive disease. It has recently been confirmed th...
journal_title:Arthritis research & therapy
pub_type: 评论,杂志文章,评审
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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doi:10.1186/ar1193
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journal_title:Arthritis research & therapy
pub_type: 评论,社论
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journal_title:Arthritis research & therapy
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更新日期:2005-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2009-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究,随机对照试验
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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