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

Kai Huang,Jia-Peng Bao,Li-Dong Wu,Gavin James Jennings

doi:10.1186/s12891-015-0595-1

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.

Highlights

Osteoarthritis (OA) is likely to become an increasing burden in the coming decades
At 4 weeks after model establishment, safranin O staining in the anterior cruciate ligament transection (ACLT) group was partially lost and fibroses were observed on the surface of hyaline cartilage, indicating loss of articular cartilage proteoglycan and induction of early OA
The ACLT animals in placebo group that were sacrificed at 9 weeks demonstrated histological features that included extensive partial thickness fissures, loss of the superficial zone layer and empty chondrocyte lacunae within the remaining cartilage with reduced Safranin-O staining, which is similar to the pathological changes in the middle stage of human OA

Summary

Introduction

Osteoarthritis (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’ , 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. The effects of weekly intra-articular injections of DHEA in preventing the progression of existing cartilage degeneration in an OA rabbit model were evaluated. DHEA has been shown to antagonize the catabolic mediators of cartilage that may exert protective effects in OA, including suppressing matrix metalloproteinases (MMPs) and inducing cartilage restoration [9]. Our recent research [10] showed that DHEA demonstrated beneficial effects on OA by influencing the balance between the aggrecanases and tissue inhibitors of metalloproteinase-3 (TIMP-3) in cartilage tissues, suggesting that DHEA might protect articular cartilage from degeneration at the molecular level.

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