Traditional Chinese medicine formulas for the treatment of osteoporosis: Implication for antiosteoporotic drug discovery

This paper reviews the latest understanding of biological and pharmacological properties of osthole (7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one), a natural product found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. In vitro and in vivo experimental results have revealed that osthole demonstrates multiple pharmacological actions including neuroprotective, osteogenic, immunomodulatory, anticancer, hepatoprotective, cardiovascular protective, and antimicrobial activities. In addition, pharmacokinetic studies showed osthole uptake and utilization are fast and efficient in body. Moreover, the mechanisms of multiple pharmacological activities of osthole are very likely related to the modulatory effect on cyclic adenosine monophosphate (cAMP) and cyclic adenosine monophosphate (cGMP) level, though some mechanisms remain unclear. This review aims to summarize the pharmacological properties of osthole and give an overview of the underlying mechanisms, which showcase its potential as a multitarget alternative medicine.

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Osthole: A Review on Its Bioactivities, Pharmacological Properties, and Potential as Alternative Medicine.

Cnidium monnieri (L.) Cuss., an annual plant of the Umbelliferae species is one of the most widely used traditional herbal medicines and its fruits have been used to treat a variety of diseases in China, Vietnam, and Japan. The aim of this review is to provide an up-to-date and comprehensive analysis of the botany, traditional uses, phytochemistry, pharmacology, toxicity and contraindication of Cnidium monnieri (L.) Cuss. and to provide future directions of research on this plant. To date, 350 compounds have been isolated and identified from Cnidium monnieri (L.) Cuss., including the main active constituent, coumarins. In vitro and in vivo studies suggest that osthole and other coumarin compounds possess wide range of pharmacological properties for the treatment of female genitals, male impotence, frigidity, skin-related diseases, and exhibit strong antipruritic, anti-allergic, antidermatophytic, antibacterial, antifungal, anti-osteoporotic effects. Although coumarins have been identified as the main active constituents responsible for the observed pharmacological effects, the molecular mechanisms of their actions are still unknown. Therefore, further studies are still required to reveal the structure-activity relationship of these active constituents. In addition, toxicological and clinical studies are also required to provide further data for pharmaceutical use.

Cnidium monnieri: A Review of Traditional Uses, Phytochemical and Ethnopharmacological Properties.

Osteoporosis treatment always aimed at keeping the balance of bone formation and bone resorption. Recently, prenyl group in natural products has been proposed as an active group to enhance the osteogenesis process. Osthole has both the prenyl group and bone-protective activities, but the relationship is still unknown. In this study we found that osthole exerted a potent ability to promote proliferation and osteogenic function of rat bone marrow stromal cells and osteoblasts, including improved cell viability, alkaline phosphatase activity, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin and osteopontin, stimulated mRNA expression of insulin-like growth factor-1, runt-related transcription factor-2, osterix, OPG (osteoprotegerin), RANKL (receptor activator for nuclear factor-κB ligand), and the ratio of OPG/RANKL, as well as increasing the formation of mineralized nodules. However, 7-methoxycoumarin had no obvious effects. Osthole also inhibited osteoclastic bone resorption to a greater extent than 7-methoxycoumarin, as shown by a lower tartrate-resistant acid phosphatase activity and lower number and smaller area of resorption pits. Our findings demonstrate that osthole could be a potential agent to stimulate bone formation and inhibit bone resorption, and the prenyl group plays an important role in these bone-protective effects.

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The importance of the prenyl group in the activities of osthole in enhancing bone formation and inhibiting bone resorption in vitro

Purpose
This study was designed to investigate the potential effect of bergapten on lipopolysaccharide (LPS)-mediated osteoclast formation, bone resorption and osteoclast survival in vitro.

Bergapten prevents lipopolysaccharide mediated osteoclast formation, bone resorption and osteoclast survival.

This study is to investigate the effect of osthol on osteoclasts' activity, bone resorption as well as apoptosis in vitro, and explore the mechanism of osthol in preventing osteoporosis. Osteoclasts were separated from long-limb bones of new born rabbits, cultured in 24-well plate with glass slices and bone slices, and treated by 1 x 10(-5) mol x L(-1) osthol. Osteoclasts were identified by observing live cells with phase contrast microscope, HE staining, TRAP staining and toluidine blue staining of bone resorption pits. The numbers of bone resorption pits were counted as well as the surface area of bone resorption on bone slice. Osteoclasts were stained with acridine orange to detect the cell apoptosis. The ratio of apoptotic osteoclasts was observed under fluorescence microscope. The gene expression of RANKL, OPG, TRAP and p-JNK1/2 protein expression were examined using real time PCR and Western blotting, respectively. Comparing with the control group without osthol, the rates of apoptotic osteoclasts increased obviously and the number and area of bone resorption pits decreased evidently with 1 x 10(-5) mol x L(-1) osthol. There is significant difference between control group and experiment group treated by 1 x 10(-5) mol x L(-1) osthol. Therefore, the osthol through RANK+RANKL/TRAF6/Mkk/JNK signal pathway inhibits the osteoclasts activity, enhances osteoclasts apoptotic and inhibits the bone resorption.

Rui-Qing Zhu

Papers

Effect of osthol on apoptosis and bone resorption of osteoclasts cultured in vitro