الفهرس 
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Abstract
Osteoarthritis (OA) is one of the oldest recorded disorders that can limits movement and cause pain which affects the quality of life of elderly and youth communities. OA of the knee joint has a higher occurrence among other types of OA and is one of the most frequent causes of knee pain due to its capacity to degrade tissues within a joint due to repeated mechanical loadings. Accordingly, interest has recently grown toward finding safe, available, and beneficial treatments against OA-related deterioration.
The present study aims to explore the effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) and curcumin-loaded poly lactic-co-glycolic acid nanoparticles (CUR-loaded PLGA NPs) as potential treatments against the OA induced by MIA on left knee joints of male rats on biochemical, molecular, and histological levels.
30 male Wistar albino rats were divided into five groups (six rats / each) designated as follows:
group I (MIA+CUR NPs + OA normal control group) The normal rats within this group were injected with the equivalent volume of saline (50 μL) in the joint of the left knees on zero, 14, 18, 22, and 26 days.
group II (MIA+BM-MSCs normal control group): The normal rats within this group were injected with the equivalent volume of the DMEM (50 μL) in the joint of the left knees on zero-day and were injected with DMEM on day14.
group III (osteoarthritic group): consists of osteoarthritic rats that received a single intraarticular injection of MIA (2 mg/50 μL) with a 21 -gauge needle into the joint of the left knee joint on zero-day.
group IV (MIA+CUR-loaded PLGA NPs): normal rats were treated with intraarticular injections of saline (50 μL) containing CUR-loaded PLGA NPs (200 mg/kg) into joints of the left knees on 14, 18, 22, and 26 days.
group V (MIA+BMMSCs): the osteoarthritic rats were treated with a single intraarticular injection (50 μL) of DMEM containing BMMSCs (5×106 cells/rat) into joints of the left knees on day 14.
On the 31st day, post-MIA administration, the rats of all groups were sacrificed under mild diethyl ether anesthesia and blood and tissue samples were collected. The clear serum was quickly removed for analysis of various biochemical parameters. While some of the tissue specimens of left knee joints were collected for histological demonstration, and the other specimens were kept at −80°C for qRT-PCR and western blot analyses.
The obtained data from the above-mentioned investigations can be summarized as the following:
MIA administration induced a significant increase in the knee diameters of the OA rats. Four intraarticular injections of CUR-loaded PLGA NPs and a single intraarticular injection of BM-MSCs markedly reduced swelling in the left knee joints.
MIA administration induced severe radiographic changes (a narrow joint space and deformed articular surface) in knee joints in the OA group. Treatment groups (MIA+BM-MSCs) and (MIA+CUR NPs) showed a little degree of narrowing, and no obvious osteophyte formation was detected.
MIA administration induced a significant increase in serum levels of pro-inflammatory cytokines (TNF-ɑ, IL-6, IL-1β, and TGF-β), MDA, and a reduction in the antioxidant defense system (SOD and GSH) compared to the normal control groups. MIA also administration induced a significant decrease in serum level of anti-inflammatory cytokines (IL-10).
Treatment groups (MIA+BM-MSCs) and (MIA+CUR NPs) revealed a significant decrease in the pro-inflammatory cytokine and MDA level, along with a significant increase in the activity of SOD and the content of GSH. Moreover, treatments notably increase IL-10 levels in the serum of OA rats.
OA rats also showed a marked elevation in the mRNA expression levels of NF-κB and iNOS, along with a significant decline in type II collagen. Additionally, MIA-treated rats demonstrated a marked increase in protein expression levels of NF-κB50, NF-κB65, and cleaved caspase-3.
Treatment groups (MIA+BM-MSCs) and (MIA+CUR NPs) significantly diminished the elevation in the mRNA expression levels of NF-κB and iNOS, along with a significant reduction in type II collagen loss. Additionally, both treatments showed a marked decrease in protein expression levels of NF-κB50, NF-κB65, and cleaved caspase-3.
Finally, Histopathological assessments of knee joints of osteoarthritic rats revealed deformity in the structure of the articular cartilage, such as clefts, disorderly arranged cells, hyperchromatic, and a reduction in chondrocyte number.
The histological lesions which resulted from MIA administration were lessened with post a single injection of BM-MSCs and four injections of CUR NPs. Both treatments showed a robust protective effect against OA histopathological changes represented by milder tissue defects and pronounced articular cartilage and subchondral bone integrity.
Overall, bone marrow-derived mesenchymal stem cells (BM-MSCs) and curcumin-loaded poly lactic-co-glycolic acid nanoparticles (CUR-loaded PLGA NPs) have potent anti-inflammatory and anti-oxidant activities in MIA-induced osteoarthritis in rats. Also, both treatments effectively inhibit the damaging actions in the articular cartilage of the knee joint of osteoarthritic rats. Thus, these treatments may be applied in the therapy of osteoarthritis after further clinical studies in human beings.