The disease-modifying effect of dehydroepiandrosterone in different stages of experimentally induced osteoarthritis: a histomorphometric study

Abstract

BackgroundOsteoarthritis (OA) is likely to become an increasing burden in the coming decades. Various agents have been developed to slow the progression of OA, and are collectively known as ‘disease-modifying drugs’, however, there is still little reliable evidence that such agents will be successful. Dehydroepiandrosterone (DHEA), a sex hormone precursor, has been recently proven as protective agent against OA, but the exact mechanism is still unkown. In the current study, the effects of weekly intra-articular injections of DHEA in preventing the progression of existing cartilage degeneration in an OA rabbit model were evaluated. The aim of the current study is to demonstrate the feature of its disease-modifying efficacy during OA progression.MethodsThirty male New Zealand white rabbits were used in this study. An anterior cruciate ligament transection (ACLT) model was used to create a progressive OA model in twenty rabbits. The animals were treated with DHEA or a placebo and were necropsied at 9 and 16 weeks. Ten rabbits receiving sham operations served as controls. The articular cartilage of the medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibial plateau (MTP) and lateral tibial plateau (LTP) was evaluated macroscopically and histologically.ResultsIn the joints of the sham-operated rabbits, few histological changes were detected on the articular surfaces of the femoral condyles and tibial plateaus. ACLT obviously induced erosive changes on the cartilage surfaces. Compared to the placebo group, the macroscopic and Mankin score analyses demonstrated that the DHEA treatment markedly reduced the cartilage lesions and delayed cartilage degeneration in the four regions of the knee at 9 weeks after operation (macroscopic score: MFC P = 0.013; LFC P = 0.048; MTP P = 0.045; LTP P = 0.02, Mankin score: MFC P = 0.012; LFC P = 0.034; MTP P = 0.016; LTP P = 0.002). At 16 weeks, DHEA demonstrated chondroprotective effects on the lateral compartment of the knee compared to the placebo group, whereas the cartilage degeneration at the medial compartment of the knee did not differ among the groups (macroscopic score: LFC P = 0.046; LTP = 0.034, Mankin score: LFC P = 0.005; LTP P = 0.002).ConclusionThe disease-modifying efficacy of DHEA aganist OA is time-specific and site-dependent. DHEA could be used as a disease-modifying strategy to limit the progression of OA, especially in the middle stage.

No Effect of Long-Term Risedronate Use on Cartilage and Subchondral Bone in an Experimental Rabbit Model of Osteoarthritis

“…As previously published, in the macroscopic evaluation of knee joint samples, we noted that the medial compartments showed slightly greater degeneration than the lateral compartments. In addition, femur also demonstrated a slightly greater deterioration than that observed in tibias (42,44). Even though some authors observed that administration of BPs showed a significant improvement in the cartilage surface and a minor number of osteophytes (3,59), in our study, risedronate did not show any improvement in the cartilage condition and did not supress the osteophyte formation.…”

“…According to previous publications, it seems that early bisphosphonate therapy may help to preserve periarticular bone properties, slowing down the short-term degeneration ( 10 , 23 , 26 ). In OA pathology, histological changes are time-dependent ( 42 ) thus, the time point of treatment initiation is crucial for treating OA and similarly, the efficacy of BPs depends on the disease stage ( 10 , 62 ). In this regard, a more beneficial effect with preventive treatment administration was observed ( 3 ).…”

“…Medial and lateral sections of the femoral condyles and tibia plateau were obtained using a band saw. Additionally, a synovial membrane fragment adjacent to the patellar ligament was obtained from each joint ( 42 ). Samples were decalcified (Osteodec, Bio-Optica, Milano, Italy), paraffin-embedded, and sectioned at 6 μm using a microtome (Leica RM 2255, Leica Biosystems, Wetzlar, Germany).…”

Histomorphometric Quantitative Evaluation of Long-Term Risedronate Use in a Knee Osteoarthritis Rabbit Model

“…Concerning the rabbit as an experimental animal model, although their histological osteoarthritic lesions have been extensively studied by the scientific community for numerous years ( 29 , 33 , 42 ), at present, there are still some differences in the parameters analyzed between preclinical studies. With reference to the anatomical location of the pathological changes, Huang et al ( 49 ) pointed out that at 16 weeks after surgery, rabbits showed partial or full thickness cartilage erosion, more marked in the MFC. These results were consistent with the results of other researches, which reported more pronounced degenerative bone changes in the femur and in the medial compartment ( 33 , 42 ).…”

Sex Steroids and Osteoarthritis: A Mendelian Randomization Study

“…However, the protective effects of E2 and DHEAS on OA occurrence are unclear. In a cohort of community-dwelling older subjects, a lower DHEAS was associated with OA irrespective of site and sex (27); and histomorphometric studies in a rabbit model of progressive OA showed that DHEAS treatment reduced cartilage lesions and delayed cartilage degeneration (28,29). DHEAS was shown to modulate the imbalance between matrix metalloproteinases (MMPs) and its inhibitors (30)(31)(32)(33); and intra-articular administration of DHEA reduced aggrecanase expression in vivo (34).…”