Osteoarthritis (OA) is one of the most common musculoskeletal disorders and a significant health concern worldwide. It may affect any hyaline cartilage containing joint. Knee is most commonly affected joint with OA and it is one of the leading causes of disability in elders. Degradation of cartilage tissue, joint space narrowing and synovitis are major signs of OA. OA is usually diagnosed by clinical symptoms like pain and lack of mobility and confirmed by radiographs. The Kellgren and Lawrence (KL) grading index is used to classify the severity of OA based on structural changes. It is considered that there is a correlation between X-ray findings and clinical symptoms of OA but in literature diverse opinions are present about the discordance between clinical and radiographic advances of disease in different ethnic groups. In the current study, the association between knee OA (KOA) radiographic evidence and its clinical outcomes were investigated in Pakistani population. One hundred and seventy subjects with diagnosed KOA were enrolled in this study. Patients were categorized into four different groups based on their radiographic disease severity determined by KL grading index. Clinical symptoms of OA were assessed using Knee injury and Osteoarthritis Outcome Score (KOOS) instrument. We have found a positive association between KOA X-rays severity and clinical symptoms like pain, symptoms and activities of daily life (ADL) (P <0.05). We have also observed an inverse relationship between health related quality of life (HR-QOL) and radiographic structural changes in KOA patients (P value <0.0001). Initially, OA was considered as a non inflammatory disease but recent evidences have suggested the involvement of certain inflammatory molecules including cytokines in OA disease progression and development. Single nucleotide polymorphisms (SNPs) in proinflammatory cytokines are also thought to play some vital role in pathology of OA. In present study, tumor necrosis factor alpha (TNF-alpha, -309 G>A, -238 G>A), Interleukin 6 (IL6, -572 G>C) and resistin (RETN, -420 C>G, +299 G>A) genetic variants were analyzed in knee OA patients (n=280) and healthy control group (n=308) to find out the involvement of these mutant genotypes in OA disease pathology in a Pakistani population. PCR coupled with restriction fragment length polymorphism (RFLP) technique was performed for genotyping investigation. Resistin is comparatively a new candidate gene in inflammatory pathologies whereas SNPs in TNF-alpha and IL6 have been explored in OA patients among different population with contradictory results. Serum resistin level was also determined by enzyme linked immunosorbent assay (ELISA) technique. A significantly positive association was found between knee OA disease and TNF-alpha (-309 G>A, -238 G>A) and IL6 (-572 G>C) polymorphisms (p<0.05). Our findings also demonstrated a considerable connection between RETN -420G variant allele (P=0.001) and KOA. RETN polymorphism at +299 G>A site also showed a positive link with OA in patients vs. controls in the studied population (P=0.01). Serum resistin levels were not notably different between patient and control group (P=0.9). Further, the serum resistin level was not observed to be affected by -420 and +299 polymorphisms and no considerable differences were noted in resistin concentration in mutant vs. wild genotypes for both the studied genetic variations. OA is a complicated and multifactorial disease. Along with primary risk factors like age, gender or genetics, mechanical stress factor is also believed to influence the OA disease development and progression. Mechanical abnormalities in any tissue of the joint may be able to trigger the OA. Though, an exact mechanism of action of OA is not fully understood yet, experimental data suggested it may be initiated by some biochemical reaction in response to mechanical stress. The abnormal mechanical load on joint may induce an extensive biochemical response via mechanotransduction, a process which convert mechanical stress into biological signals, which leads to commencement or worsening of disease. A small pilot project was also carried out to investigate the changes in cytokines gene expression in the elderly human OA-cartilage in response to the mechanical stress. Cartilage explants were taken from OA patients during joint replacement surgery. These explants were subjected to cyclic load (2s on/2s off) via a custom made loading instrument and analyzed for changes in TNF-alpha and IL6 geneexpression level. Explants, not subjected to loading were taken as control samples. Real time PCR technique was used for the determination of gene expression. 18S rRNA housekeeping gene was used for normalization of the assay. Gene expression variations were observed in different samples. A significant down regulation in IL6 and TNF-alpha mRNA levels were observed (P<0.05). This current study concludes that there is a significant association between radiographic severity of the knee OA and clinical symptoms. An inverse relation between OA severity and QOL was also demonstrated. It also showed that TNF-alpha -308 G>A and -238 G>A, RETN -420 C>G and +299 G>A, and IL6 -572 G>C may have a role in the pathogenesis of the knee OA in a Pakistani population. A noteworthy down regulationwas also detected in cartilage TNF-alpha and IL6 mRNA expression level in response to mechanical stress stimulus in our pilot experiment.