CHAPTER 1 Introduction
Total Page：16
File Type：pdf, Size：1020Kb
CHAPTER 1 Introduction Osteoporosis is the most common age-related conditions which is characterised by bone mineral density and change in microarchitecture of bone with consequently increasing in bone fragile(1). Osteoporosis has been reported to affect around 10% of population in North America, Europe and Japan(2). Considering the incidence rate of osteoporosis is anticipated to grow with increasing life expectancy. There is an extremely high mortality and morbidity due to bone fracture and loss ability to perform daily life activities. As a report from the World Health Organization (WHO) indicated the mortality and morbidity in Caucasian is as high as approximately 20% in 1-year post fracture. About 30% of survivors will have permanent disability with necessity of intensive care from others(3). For osteoporosis assessment, WHO first announced the tools for screening the patient with osteoporotic condition based on spinal mineral density (BMD) value. A person with osteoporosis has a BMD measurement of 2.5 standard deviations (SD) or more below of a young, normal adult of the same gender, according to WHO criterion(4). The International Osteoporosis Foundation (IOF) reported the project number of global osteoporotic fractures. As life expectancy continues to rise in many countries, approximately 323 million people aged 65 years or older in 1990 is predicted to surpass 1500 million by the year 2050. Together with the estimated number of hip fractures in 1990 may increase from 1.7 million to 6.3 million by the year 2050. Particularly in Asian population, the estimated number of hip fractures as 0.572 million in 1990 was expected to surpass 3.52 million by the year 2050(5). In Thailand, osteoporosis is also considered a serious public health concern resulting from long life expectancy. From previous studies, approximately 20% of postmenopausal women aged from 40 to 80 years old had osteoporotic fracture at lumbar spine, and approximately 40% of this population had osteoporotic fracture at femoral neck. Moreover, hip fracture, which is one of the most common fractures, indicated the incidence of 7.45 per 100000 in 1994(6). Phadungkiat et al.(7) reported the incidence of hip fracture in Chiang Mai province 1 as 151.2 per 100000 in 1997 and that of 181.0 per 100000 in 2006 reported by Wongtriratanachai et al(8). The incidence of hip fracture in females is 2.4 times greater than that of males. The most potent factors contributing to high mortality include non-operative treatment, delayed operative treatment, and receiving no anti-resorptive agents (3). Osteoporosis is a bone disease caused by an imbalance of bone formation and bone resorption. The rapid bone resorption can be affected by general factors that related to aging and sex hormone deficiency, leading to decreased bone formation and reduced bone quality. Especially, the rate of bone resorption resulting from the overactive osteoclasts is greater than that of bone formation. Additionally, the resorption activity of osteoclasts requires several weeks, while the formation activity of osteoblasts requires months to construct a new bone. Therefore, the osteoclastic activity inhibition is interestingly targeted for osteoporosis treatment(9). In general, the pharmacological treatment of osteoporosis is divided into two approaches, namely inhibition of bone resorption and promotion of bone formation. The medications for bone resorption inhibition include bisphosphonates, calcitonin, denosumab etc., while those to promote bone formation including parathyroid hormones etc(3). A bisphosphonate drug is currently the most popular agent used for prevention of osteoporotic fracture and treatment of osteoporosis. Unfortunately, bisphosphonates were reported to cause many side effects such as digestive problems, flu-like symptoms, bone pain and skin rash.(10) Additionally, the reduced bone resorption by using anti-resorptive agent cooccurs with the reduced bone formation, resulting from their coupling signal. Hence, a novel scheme for development of osteoporotic agents is mainly focused to inhibit bone resorption but no effect to bone formation. Regards to new findings from previous literatures, bone resorption by osteoclasts is complex and multi-step processes such as the attachment of osteoclasts to bone surface using an integrin receptor prior to bone degradation. During bone resorbing process, osteoclasts release proton ions through membrane into the site of degraded bone via V-ATPase for acidifying the microenvironment, and also secrete the protease enzymes into resorption lacuna. These proteins are considered as targets for development of the osteoporotic agents(9, 11). Not only the medications used to treat the osteoporotic condition, but medicinal plants also used as osteoporotic prevention such as Traditional Chinese Medicines (TCMs). TCMs is 2 a broad range of medicinal resource in China, which is mostly used to treat various diseases. According to the rapid development of extraction and separation process, a large number of compounds have been identified. Many of them are proven to be active in various biological assessments.(12) The phytochemical compounds possess the osteoprotective property including flavanones, flavones, flavonols etc(13). These herbal compounds exhibited the beneficial activities to represent as the alternative medicines together with calcium and vitamin D for osteoporotic prevention in early stages. Accordingly, natural products have made a significant contribution to drug discovery and nearly half of novel drugs in the market are natural products and their derivatives. The herbal compounds have received increasing attention due to their specific pharmacological activities(14). Hence, the herbal compounds can be used for development the anti-osteoporotic agents toward various targets on osteoclast. In drug discovery and development, target discovery is an important step in drug discovery process(15) . Interestingly, the agents that can inhibit the function of protein at several targets seem extremely to be a key factor for new drug development. These agents called multi- target agents. Multi-target agents are recently highlighted due to using modern approaches to identify drugs that hit the multiple targets. The main reasons need for the better and safer drugs because the concurrent drugs cannot meet therapeutic target due to their complex diseases such as cancers, autoimmune diseases, and low success rate of drug development that calls for better and safer drug(16). As previous reports, approximately 20 new drugs were launched into the market per year because approximately 90% of new drugs failed in first-in-human testing. Especially in cancer disease, the percentage of drug development failure is highly around 95% in human testing due to their poor safety and less efficacy, which is accounting for 30% of all failures. Therefore, to increase the successful of drug development, the better targets are required. Together with the novel approach, the drug hitting multiple targets might be more successful in drug development(16). A good example of multi-target agents is sunitinib. Sunitinib is an ATP-mimetic kinase inhibitor that binds to the active binding site of several kinase enzymes resulting in enzyme activation and autophosphorylation inhibition(16). Although the multi-target approach is naturally associated with toxicology and off-target side effects, it can be argued that multi-target agents would have a larger therapeutic index than those hitting a single target. Therefore, the multi-target agent could prove to be safer drug. In order to investigate herbal compounds toward several targets on osteoclasts, the combining various approaches including in silico and in vitro methods have been done to find the hit compounds for further developments as multi-target agents against bone resorption process. 3 1.2 Objectives This study aims to: 1. To construct an in-house library of natural compounds with anti-osteoresorptive activity 2. To investigate potential multi-target compounds against the selected targets namely V-ATPase, and cathepsin K 4 CHAPTER 2 Literature reviews 2.1 Bone 2.1.1 Bone biology and function(17) Bone is a living, dynamic connective tissue that is continuously remodelled throughout life. Bone is made of approximately 80% of dense cortical bone and 20% of trabecular bone (Figure.1). The most apparent functions of bone are to provide structural support for the body, protect the internal organs, and also act as a reservoir of mineral. Generally, bone composes of two phases including mineral phase and organic phase. In mineral phase, the most component is hydroxyapatite, whereas in organic phase the most component is type I collagen (approximately 90%), non-collagenous protein (NCPs), lipids and water. Figure 2.1. Bone structure 2.1.2 Bone modelling and remodeling Bone modelling (9, 17) The skeleton undergoes longitudinal and radial growth, modelling and remodeling throughout life. During embryogenesis, the flat bones are formed by mesenchymal stem cells 5 whilst long bones are established early as cartilages that become gradually replaced by bone. During childhood, bone modelling occurs as a result of the change of bone shaping due to mechanical forces applied on the skeleton. Bone remodeling, including bone resorption and bone formation, also occurs during childhood. Whilst in adulthood bone remodeling is notable process to maintain bone strength. Bone formation and bone resorption are less tightly coupled during modelling than remodeling.