Details

Autor(en) / Beteiligte

• Rabie, Mostafa A.
• Sayed, Rabab H.
• Venkatesan, Jagadeesh K.
• Madry, Henning
• Cucchiarini, Magali
• El Sayed, Nesrine S.

Titel

Intra-articular injection of rAAV-hFGF-2 ameliorates monosodium iodoacetate-induced osteoarthritis in rats via inhibiting TLR-4 signaling and activating TIMP-1

Ist Teil von

• Toxicology and applied pharmacology, 2023-01, Vol.459, p.116361, Article 116361

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Osteoarthritis (OA) is a chronic debilitating degenerative disorder leading to structural, and functional anomaly of the joint. The present study tests the hypothesis that overexpression of the basic fibroblast growth factor (FGF-2) via direct rAAV-mediated gene transfer suppresses monosodium iodoacetate (MIA)-induced knee OA in rats relative to control (reporter rAAV-lacZ vector) gene transfer by intra-articular injection. Rats were treated with 20 μl rAAV-hFGF-2 on weekly basis; on days 7, 14, and 21 after single intra-articular injection of MIA (3 mg/50 μl saline). FGF-2 reduced knee joint swelling and improved motor performance and muscle coordination as evidenced by increased distance travelled, mean speed, rearing frequency in open field test (OFT) as well as fall-off latency in rotarod test together with reduced immobility time in OFT. Moreover, FGF-2 attenuated MIA-related radiological and histological alterations. Indeed, FGF-2 decreased knee joint inflammatory biomarker as demonstrated by reduced mRNA expression of toll like receptor (TLR)-4 and its downstream mediators such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and high motility group box (HMGB) 1. In parallel, FGF-2 attenuated knee joint degradation biomarkers as reflected by the downregulation of ADAMTS-5 mRNA expression and matrix metalloproteinase 13 (MMP-13) content together with the up-regulation of tissue inhibitor of metalloproteinase (TIMP)-1 mRNA expression. These findings suggest a potential therapeutic role for FGF-2 against MIA-induced knee OA in rats via inhibition of TLR4 signaling and activating TIMP-1, resulting in down-regulation of ADAMTS-5 and MMP-13. •FGF-2 reduced knee joint swelling and improved motor performance.•FGF-2 attenuated MIA-related radiological and histological alterations.•FGF-2 reduced TLR-4 expression and its downstream mediators; TNF-α, IL-1β and HMGB.•FGF-2 downregulated ADAMTS-5 mRNA expression and MMP-13 content•FGF-2 attenuated knee joint degradation and upregulated TIMP-1 mRNA expression.