OBJECTIVE: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential.
DISCUSSION: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans.
CONCLUSION: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.
AIM OF THE STUDY: To evaluate the effects of EL on the time-mannered sequential proliferative, differentiative, and morphogenic modulation in osteoblasts compared with testosterone.
MATERIALS AND METHODS: Cell proliferation was analysed using MTS assay and phase contrast microscopy. Osteogenic differentiation of MC3T3-E1 cells was assessed through a series of characteristic assays which include crystal violet staining, alkaline phosphatase (ALP) activity and Van Gieson staining. Taken together, the bone mineralization of extra cellular matrix (ECM) was estimated using alizarin red s (ARS) staining, von kossa staining, scanning electron microscopic (SEM) and energy dispersive x-ray (EDX) analysis.
RESULTS: The cell proliferation data clearly revealed the efficiency of EL particularly at a dose of 25µg/mL, in improving the growth of MC3T3-E1 cells compared with the untreated cells. Data also showed the prominence of EL in significantly promoting ALP activity throughout the entire duration of treatment compared with the testosterone-treated cells. The osteogenic differentiation potential of EL was further explored by analysing mineralization data which revealed that the calcified nodule formation (calcium deposition) and phosphate deposition was more pronounced in cells treated with 25µg/mL concentration of EL at various time points compared with the untreated and testosterone treated cells. The scanning electron microscopic (SEM) analysis also revealed highest globular masses of mineral deposits (identified as white colour crystals) in the ECM of cultured cells treated with 25µg/mL concentration of EL.
CONCLUSION: Compared to testosterone, greater potential of EL in promoting the proliferation and osteogenic differentiation of MC3T3-E1 cells provides an in vitro basis for the prevention of male osteoporosis. Thus, we anticipate that EL can be considered as an alternative approach to testosterone replacement therapy (TRT) for the treatment of male osteoporosis.