|Bone is a dynamic tissue that undergoes continual adaptation during vertebrate life to attain and preserve skeletal size, shape, and structural integrity and to regulate mineral homeostasis. Two processes, remodeling and modeling, underpin development and maintenance of the skeletal system . Bone modeling is responsible for growth and mechanically induced adaptation of bone and requires the processes of bone formation and bone removal (resorption). Bone remodeling is responsible for removal and repair of damaged bone to maintain integrity of the adult skeletal and mineral homeostasis. The process of bone remodeling to make bone is unique among organs and tissues, and it is complexity with respect to interactions along the remodeling sequence by systemic influences, stress action, growth factors and cytokines [2,3]. Bone homeostasis, which maintains bone mass, is skillfully regulated through osteoclasts, osteoblasts and osteocytes, which are major cells in bone tissues. This process is regulated through various physiological systems and it is disturbed through various pathophysiological states.
|Osteoblasts, which are differentiated from bone marrow mesenchymal stem cells, stimulate bone formation and calcification, while osteoclasts, which develop from hematopoietic progenitors, promote bone resorption [1-3]. In the physiologic process of bone turnover, a resorptive stimulus firstly triggers recruitment of osteoclasts to a site on the bone surface. Osteoclasts, which develop from hematopoietic progenitors, are recruited to the site and excavate the calcified matrix. After resorbed lacunar pit is filled with new osteoid, osteoblasts become flatter and less active, with the final newly remodeled bone surface lined by flat lining cells. Remodeling of cancellous bone begins with the retraction of lining cells that cover the bone surface. Then, the cavity is refilled by osteoblasts via a process that occurs in three distinct phases: initiation, progression and termination . During the initiation phase, a team of osteoblasts arising from local mesenchymal stem cells assembles at the bottom of the cavity and bone formation begins. As bone formation progresses, some osteoblasts are entombed within the matrix as osteocytes but the majority dies by apoptosis. Bone formation terminates when the cavity has been refilled, at which time the few osteoblasts that remain become the flat lining cells that cover the quiescent surfaces of bone. Once formed, few osteocytes die. Their viability is likely maintained by physiological levels of mechanical stimulation. When mechanical forces are reduced, for example in weightlessness, osteocytes die by apoptosis. This event appears to act as a beacon for osteoclast recruitment and generation of a new basic multicellular unit, which in turn replaces the old bone containing dead osteocytes with new bone containing viable osteocytes.
|Bone acts as major storage site for growth factors, which are produced by osteoblasts, diffuse into newly deposited osteoid and are stored in the bone matrix including isulin-like growth factors (IGFI and II), transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF), or bone morphologic proteins (BMPs) [4,5]. These bone-derived factors, which can be liberated during subsequent periods of bone resorption, act in an autocrine, paracrine, or delayed paracrine fashion in the local microenvironment of the bone surface.
|Bone mass with increasing ages is reduced by decrease in osteoblactic bone formation and increase in osteoclastic bone resorption, inducing osteoporosis. The most dramatic expression of osteoporosis is represented by fractures of the proximal femur for which the number increases as the population ages [6,7]. Osteoporosis is characterized by reduced bone strength and an increased risk for lowtrauma fractures. Bone mass is dramatically reduced after menopause, which depresses the secretion of ovarian hormone (estrogen) in women . Deficiency of estrogen advances osteoclastic bone resorption. This is very important as a primary osteoporosis. Postmenopausal osteoporosis, a consequence of ovarian hormone deficiency, is the archetypal osteoporotic condition in women after menopause and leads to bone destruction through complex and diverse metabolic and biochemical changes. About 40% of women in developed countries will experience an osteoporosis-related fracture in the course of their lifetime, with men experiencing approximately one-third to one-half the risk of women. Thus, osteoporosis is a major cause of increased morbidity and mortality affecting the aging population.
|Osteoporosis has also been shown to induce after diabetes (type I and II), obesity, inflammatory disease, and various pathophysiological states. Diabetic osteoporosis is noticed in recent years [9,10]. Diabetes is frequent in the elderly, and therefore frequently coexists with osteoporosis. Furthermore, there has also been a global increase in the prevalence of obesity, with obesity-related diabetes currently affecting over 366 million adults worldwide and projections that this will reach 552 million by 2030 . Type 1 diabetes, and more recently type 2 diabetes, has been associated with increased fracture risk. In Western societies, mean body weight has dramatically increased in older people, and a similar trend exists in Asia. Yet insufficient attention has been directed to the problem of osteoporotic fractures in the overweight and obese. Osteoporotic fractures occur in overweight or obese people, and obese men may be particularly susceptible [12,13]. The National Health and Nutrition Examination Survey have reported that 63% of osteoporotic patients have hyperlipidemia. Epidemiological studies reveal an inverse relationship between serum cholesterol levels and bone mineral content and density, independent of age and body mass index. Diet-induced hyperlipidemia is also associated with a reduction in bone mineral content and density in animals [12,13]. Hyperlipidemia induces secondary hyperparathyroidism and impairs bone regeneration and mechanical strength.
|It will be important to prevent and treat osteoporosis. Antiresorptive agents have long been the preferred standard of care for the amelioration of bone loss, because the processes of bone resorption and bone formation are tightly “coupled”, anti-resorptive therapies are also observed clinically to simultaneously suppress bone formation leading to a “low bone turnover state”. Although in general anti-resorptive agents do an excellent job of preventing additional bone loss, they do not allow for adequate regeneration of lost bone mass. Drugs, which are used clinically in the treatment of osteoporosis, are mainly based on the action of osteoclastic bone resorption. An intensive effort has begun to identify or develop anabolic agents capable of rebuilding lost bone mineral density. At present teriparatide, a fragment of human parathyroid hormone is only the United State Food and Drug Administration (FDA) approved anabolic agent currently available. This agent represents a significant leap forward but as a biologic based agent its use is limited by high cost and the need for daily injection. Furthermore, therapy is not recommended for more than 2 years due to the potential for osteosarcoma. As a consequence, there is intense interest in the identification of additional anabolic agents. Clinical compounds that stimulate bone formation are under development.
|There is growing evidence that functional food factors (biomedical food factors) regulate bone homeostasis and that have beneficial effects in the prevention and treatment of osteoporosis [14,15]. This may be important in maintaining bone health in long life. Chemical factors, which reveal osteogenic effects, are found in various food and plants. These factors may be useful in the therapy of osteoporosis. It has been expected that studies of the chemical structure-related activity of biofactors from food and plants will lead to the development of new drugs that stimulate bone formation and inhibit bone resorption. Analogues, which are synthesized with origination of bioactive chemicals derived from food factors, may be developed as novel drugs that reveal potent-osteogenic effects for the treatment of osteolysis, which is induced in various diseases including osteoporosis, inflammation, obesity, diabetes, cancer cell bone metastasis, and bone fracture.
|The author et al. has focused on the role of functional food factors in the prevention and treatment of osteoporosis since year 1984. Zinc, an essential trace element, has been demonstrated to reveal stimulatory effects on osteoblastic bone formation and suppressive effects on osteoclastic bone resorption , thereby increasing bone mass. After that, isoflavone (including genistein and daidzein), which are contained in soybean, and menaquinone-7, an analogue of vitamin K2 which is abundant in fermented soybeans, have been shown to stimulate osteoblastic bone formation and to inhibit osteoblastic bone resorption [17-21]. Moreover, among various carotenoids (including lutein, lycopene, β-carotein, and astaxanthin), β-cryptoxanthin, which is largely in Satuma mandarin (C. unchiu MARC), has been found to uniquely have stimulatory effects on osteoblastic bone formation and suppressive effects on osteoblastic bone resorption [22-24]. Moreover, flavonoid p-hydroxycinnamic acid, which is present in many plant and fruits, has also been shown to reveal an osteogenic effect on bone, whereas other cinnamic acid-related compounds do not have an effect on bone [25,26]. Our findings were the first time in this field. These factors have been found to regulate gene expression of various proteins that are related to the regulation of osteoblastic and osteoclastic cell functions. This was partly contributed to the clarification of a new molecular mechanism in the regulation of bone homeostasis.
|Supplementation of zinc, genistein, menaquinone-7, β-cryptoxanthin and p-hydroxycinnamic acid has been shown to have restorative effects on bone loss induced in ovariectomized rats, which are an animal model of osteoporosis, due to stimulating osteoblastic bone formation and suppressing osteoclastic bone resorption. Moreover, supplemental intake of these factors has been demonstrated to have anabolic effects on bone metabolism in humans including postmenopausal women. Thus, food chemical factors may play an important role in bone health and osteoporosis prevention with increasing age and various pathophysiologic states. Interestingly, the osteogenic effects of vitamin D3, vitamin K2 (menaquinone-7), and genistein have been demonstrated to synergistically enhance with the combination of zinc [27-32]. Supplements with chemically pure ingredients of biomedical food factors, which have potential osteogenic effects, will be expected to use as new drug for osteoporosis . Biomedical osteoporosis treatment with osteogenic factors may be important clinically .
|The author was partly supported by Awards of the Mishima Kaiun Memorial Foundation (Japan), the Senji Miyata Foundation (Japan), and the Japan Society for Biomedical Research on Trace Elements.
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