Suppression of pain and joint destruction by inhibition of the proteasome system in experimental osteoarthritis.
Osteoarthritis is a degenerative joint disease with pain and loss of joint function as major pathological features. Recent studies show that proteasome inhibitors reduce pain in various pathological conditions. We evaluated the effects of MG132, a reversible proteasome inhibitor on pain and joint destruction in a rat model of osteoarthritis. Osteoarthritis was induced by intraarticular injection of monosodium iodoacetate into the rat knee. Knee joint stiffness was scored and nociception was evaluated by mechanical pressure applied to the respective hind paw. Knee joint destruction was assessed by radiological and histological analyses. Expression of matrix metalloproteinase-3 (MMP-3) was analyzed by quantitative reverse transcription polymerase chain reaction in the knee articular cartilage. Expression of substance P (SP) and calcitonin gene-related peptide (CGRP) was studied in the dorsal root ganglia (L4-L6) by quantitative reverse transcription polymerase chain reaction and in the knee joints by immunohistochemistry. Our results indicate that daily treatment of osteoarthritic rats with MG132 significantly increases their mobility while the swelling, pain thresholds, and pathological features of the affected joints were reduced. Furthermore, the upregulated expression of MMP-3, SP, and CGRP in the arthritic rats was normalized by MG132 administration. We conclude that the proteasome inhibitor MG132 reduces pain and joint destruction, probably by involving the peripheral nervous system, and that changes in SP and CGRP expression correlate with alterations in behavioural responses. Our findings suggest that nontoxic proteasome inhibitors may represent a novel pharmacotherapy for osteoarthritis.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm 17176, Sweden Department of Medicine, Centre for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm 17176, Sweden Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm 18288, Sweden Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 75105, Sweden Department of Neurobiology, Care Sciences and Society, Center for Family and Community Medicine, Karolinska Institutet, Huddinge 14183, Sweden.
Aisha Siddiqah
AS
Ahmed
Jian
J
Li
Helena
H
Erlandsson-Harris
André
A
Stark
Georgy
G
Bakalkin
Mahmood
M
Ahmed
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007719:Knee Joint / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007976:Leupeptins / Q000494:pharmacology / Q000627:therapeutic use*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D051381:Rats; D011917:Rats, Inbred Lew; D013373:Substance P / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D013373:Substance P; D019278:Matrix Metalloproteinase 3; D015740:Calcitonin Gene-Related Peptide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde