## 4 Discussion  
The primary approach in the clinical treatment of OA involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and hyaluron, which allow for symptomatic relief but provide no apparent disease-modifying effects [3]. In some instances, NSAIDs may even have deleterious effects, as they inhibit the synthesis of proteoglycan, which plays a crucial role in maintaining the functions of the cartilage. Therefore, there is a critical need to develop alternative agents that can prevent the destruction of cartilage or stimulate their proper repair [6; 8]. OA is the most prevalent articular disease in the elderly [1] and is characterized by loss of articular cartilage components, leading to tissue destruction and hypocellularity, eventually resulting in loss of joint function [19; 27]. Alternative agents that can prevent the destruction of cartilage or stimulate its proper repair are needed [6] due to the deleterious effects of NSAIDs [3]. In this study, anti-arthritis effects were evaluated from PS with high anti-oxidative [30] and anti-inflammatory effects [32]. The active components of PS comprise flavonoids and phenolic acid [34; 35]. These materials are known to have antioxidant and anti-inflammatory effects, and the inflammation may be controlled by reducing nitric oxide generation [39]. [PERSON]'s 12-point histopathological grading system of cartilage deterioration is based on cartilage surface damage, the number of chondrocytes, and Safranin O staining. In this study, normal cartilage was scored as 0 in the control CON group; the most severe case of cartilage deterioration had a high score of 10.8 in the NC group (Table 5) as shown in the previous report [22]. OA control rats (NC) showed marked increases in surface cartilage damage, decreases in chondrocytes, and clone formations on both femur and tibia AC when compared with those of normal control rats (CON). In addition, NC also showed significant decreases in the mean femur and tibia AC thicknesses, and increases in SM epithelial thicknesses and inflammatory cell numbers infiltrated around the SM/IFP as compared to those of the CON, suggesting classic OA histopathological lesions. Inflammation and fibrosis presented in SM/IFP. However, these histopathological surgically induced histopathological OA lesions were obviously and most significantly inhibited by PC and PS treatments in a dose-dependent manner. PS2 showed more favorable inhibitory effects than those of the commercial reference (PC), and PS1 was comparable to the anti-OA effects of PC (Figure 3, Table 5). In the previous trial using a mixture of dried pomergnate concentrate powder, eucommiae cortex, and achyranthis radix, this improved the decreases in AC thickness and the number of chondrocytes detected in OA rats [22]. OA is the most common clinical syndrome of joint pain accompanied by varying degrees of functional limitation [4]. PS inhibited the inflammatory response in human rheumatoid synovial  
Figure 7: Effects of PS on cytokines expression in the cartilage with synovial membrane of OA rats. (**a**) MMP-2, (**b**) MMP-3, and (**c**) MMP-9. Data are expressed as the mean \(\pm\) SE (n = 4/group). CON: normal sham control; NC: negative control; PC: positive control; PS1: PS at 100 mg/kg BW; PS2: PS at 300 mg/kg BW. NC group was significantly different from the CON group at *** \(p<0.001\) by Student’s \(t\) test. \({}^{a<}\) Mean values with different letters are significantly different (\(p<0.05\)) among groups by [PERSON]’s multiple range test. fibroblasts and a murine model of arthritis [33]. Thus, effects of PS on joint pain in a rat model of surgically induced OA and comparisons of the mechanisms in different arthritis models should be measured in future studies [40]. OA is a debilitating disease that affects the AC and subchondral bone, and inflammation is closely involved in all steps of OA progression [39]. The inflammatory factors TNF-\(\alpha\), IL-1\(\beta\), and IL-6 contribute to OA progression [41].