Masanori Somei

Novel bromomelatonin derivatives as potentially effective drugs to treat bone diseases

Abstract:u2002 Several reports indicate that melatonin is involved in the regulation of bone metabolism. To examine the direct effect of melatonin on osteoclasts and osteoblasts, we developed an in vitro assay using fish scales that contain osteoclasts, osteoblasts, and bone matrix, all of which are similar to those found in mammalian membrane bone. Using the assay, we demonstrated that melatonin suppressed osteoclastic and osteoblastic activities. These findings are in agreement with the reports from in vivo studies in mice and rats. In an attempt to develop molecules that increase bone mass, novel bromomelatonin derivatives were synthesized, and the effects of these chemicals on osteoclasts and osteoblasts using the scale assay were examined. As a result, novel bromomelatonin derivatives with the ability to possibly increase bone formation were identified. In scale osteoclasts, particularly, 1‐benzyl‐2,4,6‐tribromomelatonin had a more potent activity than melatonin. In reference to osteoblasts, this agent (10−9–10−6u2003m) significantly activated osteoblasts. The effect of 1‐benzyl‐2,4,6‐tribromomelatonin on bone formation was confirmed in ovariectomized rats. Thus, the oral administration of 1‐benzyl‐2,4,6‐tribromomelatonin augmented the total bone mineral density of the femoral metaphysis of ovariectomized rats. The stress–strain index of the diaphysis in 1‐benzyl‐2,4,6‐tribromomelatonin‐treated rats significantly increased in comparison with that in ovariectomized rats. In rats fed a low‐calcium diet, the total bone mineral density of the femoral metaphysis significantly increased following the oral administration of 1‐benzyl‐2,4,6‐tribromomelatonin. These studies identified a melatonin derivative that may have potential use in the treatment of bone diseases, such as osteoporosis.

Novel bromomelatonin derivatives suppress osteoclastic activity and increase osteoblastic activity: implications for the treatment of bone diseases.

Abstract:u2002 The teleost scale is a calcified tissue that contains osteoclasts, osteoblasts, and bone matrix, all of which are similar to those found in mammalian membrane bone. Using the goldfish scale, we recently developed a new in vitro assay system and previously demonstrated that melatonin suppressed both osteoclastic and osteoblastic activities in this assay system. In mammals, 2‐bromomelatonin possesses a higher affinity for the melatonin receptor than does melatonin. Using a newly developed synthetic method, we synthesized 2‐bromomelatonin, 2,4,6‐tribromomelatonin and novel bromomelatonin derivatives (1‐allyl‐2,4,6‐tribromomelatonin, 1‐propargyl‐2,4,6‐tribromomelatonin, 1‐benzyl‐2,4,6‐tribromomelatonin, and 2,4,6,7‐tetrabromomelatonin) and then examined the effects of these chemicals on osteoclasts and osteoblasts. All bromomelatonin derivatives, as well as melatonin, had an inhibitory action on osteoclasts. In particular, 1‐benzyl‐2,4,6‐tribromomelatonin (benzyl‐tribromomelatonin) possessed a stronger activity than melatonin. At an in vitro concentration of 10−10u2003m, benzyl‐tribromomelatonin still suppressed osteoclastic activity after 6u2003hr of incubation. In reference to osteoblasts, all bromomelatonin derivatives had a stimulatory action, although melatonin inhibited osteoblastic activity. In addition, estrogen receptor mRNA expression (an osteoblastic marker) was increased in benzyl‐tribromomelatonin (10−7u2003m)‐treated scales. Taken together, the present results strongly suggest that these novel melatonin derivatives have significant potential for use as beneficial drug for bone diseases such as osteoporosis.

Current status of drug therapies for osteoporosis and the search for stem cells adapted for bone regenerative medicine

A number of factors can lead to bone disorders such as osteoporosis, in which the balance of bone resorption vs. bone formation is upset (i.e., more bone is resorbed than is formed). The result is a loss of bone mass, with a concomitant decrease in bone density. Drugs for osteoporosis can be broadly classified as “bone resorption inhibitors”, which impede bone resorption by osteoclasts, and “bone formation accelerators”, which augment bone formation by osteoblasts. Here, we describe representative drugs in each class, i.e., the bisphosphonates and the parathyroid hormone. In addition, we introduce two novel bone formation accelerators, SST-VEDI and SSH-BMI, which are currently under investigation by our research group. On the other hand, regenerative therapy, characterized by (ideally) the use of a patient’s own cells to regenerate lost tissue, is now a matter of global interest. At present, candidate cell sources for regenerative therapy include embryonic stem cells (created from embryos based on the fertilization of oocytes), induced pluripotent stem cells (created artificially by using somatic cells as the starting material), and somatic stem cells (found in the tissues of the adult body). This review summarizes the identifying features and the therapeutic potential of each of these stem cell types for bone regenerative medicine. Although a number of different kinds of somatic stem cells have been reported, we turn our attention toward two that are of particular interest for prospective applications in bone repair: the dedifferentiated fat cell, and the deciduous dental pulp-derived stem cell.

Inhibitory Effects of a Tryptamine Derivative on Ultraviolet Radiation–Induced Apoptosis in MC3T3-E1 Mouse Osteoblasts

MS-IPA1 is a new synthetic compound that is synthesized from tryptamine. Recently, our group demonstrated that SST-VED-I-1, which has a similar chemical structure to MS-IPA1, inhibits starvation-induced apoptosis in osteoblasts. However, the effects of MS-IPA1 on apoptosis in osteoblasts have not yet been examined. Therefore, this study examined the effects of this compound on apoptosis in osteoblasts. In this study, MC3T3-E1 mouse osteoblasts were used and apoptosis was induced by ultraviolet radiation (UV). We investigated the effect of MS-IPA1 on apoptosis by analyzing caspase3/7 activity, translocation of phosphatidylserine (PS), and mRNA expression levels of Bcl-2 and Bax. In addition, it was investigated whether MS-IPA1 affects cell proliferation and cell cycle progression. We found that MS-IPA1 had no effect on cell proliferation or cell cycle progression. However, MS-IPA1 suppressed UV-induced cell death in a dose-dependent manner, which was accompanied with the inhibition of caspase activation and translocation of PS. Furthermore, after UV exposure, Bcl-2 expression was increased in the MS-IPA1-treated cells as compared to that in the vehicle-treated cells. In contrast, Bax expression was decreased in the MS-IPA1-treated cell as compared to that in the vehicle-treated cells. These results suggest that MS-IPA1 has an inhibitory effect on apoptosis in osteoblasts through a Bcl-2 family-dependent signaling pathway.