Effect Of Dehydroepiandrosterone On Experimental Osteoarthritis In Rabbits

BackgroundOsteoarthritis (OA) is one of the most common diseases in the elderly. Epidemiological investigation shows that the number of OA patients is increased at a striking speed. Although the initial causes of OA are still obscure, the mechanism of cartilage degradation has been extensively investigated, and it is now generally agreed that cartilage degradation is a process resulting from an imbalance of anabolic and catabolic changes in the articular cartilage matrix. The process involves many biochemical mediators such as matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and interleukin-1 beta (IL-1β).An ideal therapeutic agent for OA would prevent or retard the progression of established OA by reducing or, preferably, reversing the underlying pathologic processes (structure modifying), resulting in the retention or restoration of more normal articular cartilage function. Current pharmacotherapy of OA is limited to improve the symptom but these interventions do not possess structure modifying activities.Dehydroepiandrosterone (DHEA) is the most abundant steroids in the human plasma. Because the plasma level of DHEA declines with age, the diverse biological functions of DHEA in humans have become an area of intense interest and research. Previous studies suggest that DHEA has protective effects on body functions and against diseases such as bone loss, atherosclerosis, systemic lupus,cancer, and diabetes mellitus. Recently, it has been demonstrated that DHEA has a protective role against articular cartilage loss. However, there is little information about the effects of DHEA on OA and the mechanisms of the effect of DHEA on OA remain to be identified.ObjectiveIn this study, we investigated the effect of DHEA on OA in rabbits induced by transection of anterior cruciate ligament (ACLT) and studied the mechanisms: mRNA expressions of MMP-3, TIMP-1 and IL-ip were assessed in the cartilage and synovium of an experimental rabbit model of OA.Materials and methods1. Forty rabbits underwent ACLT and were divided into two groups randomly.2. Experimental rabbits were injected with lOOumol/L DHEA resolved in the dimethylsulphoxide in the knees 4 weeks after transaction, once a week for five weeks. Rabbits in control group were treated under the same condition using dimethylsulphoxide.3. All rabbits were killed 9 weeks after ACLT and the knee joints wereevaluated by gross morphology and histology.4. The mRNA expressions of MMP-3, TIMP-1 and IL-ip in the cartilageand synovium was analyzed using reverse transcription polymerase chain reaction(RT-PCR).Results1. Macroscopic cartilage assessment showed that the extent and grade of cartilage damage in the DHEA group were less severe than in the control group, but this difference was not significant/^ 0.05/ 2. Cartilages from the control group exhibited morphologic changes,including fibrillation, hypocellularity, and loss of Safranin O staining. Insynovial tissue, hyperplasia and hypertrophy of synovial lining cells,infiltration of inflammatory cells, proliferation of granulation tissue, andvascularization were noted in the control group, (both P<0.05)3. The mRNA expression of MMP-3 in cartilage and synovium decreasedsignificantly in experimental group (both PO.05). The mRNA expressionof TIMP-1 in cartilage and synovium increased significantly inexperimental group compared with that in control group (both P<0.05).No significant difference of IL-ip mRNA expression in the cartilage wasfound between experimental and control groups (P>0.05). The mRNAexpression of IL-ip was significantly suppressed in experimental groupcompared with that in control group (PO.01).Conclusion1. 100umol/L DHEA protects against cartilage degradation, alleviates theinflammation of synovium and inhibits the progression of osteoarthritis in experimental model.2. The following are likely mechanism of DHEA on OA:(1) Down-regulating the level of MMP-3 and up-regulating the level of TIMP-1 in the cartilage and synovium protects against cartilage destruction and inhibits the progression of OA.(2) Down-regulating the level of IL-ip in the synovium, inhibit inflammation reaction and protect the cartilage degradation.