Biol. Pharm. Bull. 29(2) 297—301 (2006)

characterized with low or no insulin production, which sometimes leads to diabetic osteopenia and osteoporosis. In the absence of insulin, insulin-sensitive cells exhibit marked reduction of glucose uptake activity, resulting in increased serum glucose levels and subsequent development of a variety of diabetic complications. Histological and bone marker assessments indicate a low turnover state in bone formation rate and decreased osteoblastic activity in rat models of type I diabetes. In addition, there is a report about the close relationship between the bone loss and the fasting blood glucose level. The occurrence of hyperglycemic bone loss is controversial because not only high glucose but also other factors including insulin deficiency could mediate bone loss in IDDM patients, however, while little is known about the direct effect of hyperglycemia on bone metabolism. By contrast, in vitro analysis reveals the induction by hyperglycemia of osteoblastic dysfunctions. In human osteosarcoma (MG63) cells cultured under high glucose conditions ( 55 mM), for example, impaired response is seen to parathyroid hormone and to 1,25-dihydroxyvitamin D3, an active form of vitamin D3, required for the synthesis of the matured osteoblast marker protein osteocalcin. Other reports using calvarial osteoblastic cell line MC3T3-E1 cells have demonstrated that high glucose ( 15.5 mM) inhibits Ca intake and bone mineralization with an increase in both cellular proliferation and alkaline phosphatase (ALP) activity. These findings indicate that elevated extracellular glucose concentrations would directly impair osteoblastic functions resulting in defective mineralization similar to clinical findings. Therefore, these in vitro analyses are useful for the better understanding of mechanisms relevant to osteoblastic malfunctions associated with diabetes mellitus. On the other hand, we have previously reported the possible functional expression of particular GABAergic signaling machineries in cultured rat calvarial osteoblasts. GABA is known as one of the most abundant inhibitory amino acid neurotransmitters in the mammalian central nervous system (CNS). In the CNS, GABA is supposed to mediate inhibitory neurotransmission thorough different signaling machineries including GABA synthase, GABA receptors and GABA transporters. These GABAergic machineries are found not only in the CNS but also in some non-neuronal and peripheral organs such as heart, lung, kidney, adrenal, pancreas, liver, spleen and uterus. In addition to these peripheral tissues, the expression of GABA and particular GABAergic signaling molecules is found in bone cells such as osteoblasts and chondrocytes. Amongst different isoforms of GABA transporters required for signal termination, expression of betaine/GABA transporter-1 (BGT-1) is exclusively detected at mRNA and protein levels with a temperature-, sodiumand chloride-dependent activity of [H]GABA accumulation in osteoblasts, as well as GABAB receptor. Although GABAB receptor is shown to play an inhibitory role in osteoblastic differentiation and/or maturation, the role of BGT-1 isoform has not yet been well understood. In this study, therefore, we have attempted to demonstrate the possible relationship between GABA transport mediated by BGT-1 isoform and osteoblastic dysfunctions using [H]GABA accumulation in osteoblasts cultured under hyperglycemic conditions as a cellular model for osteopenia seen under hyperglycemia. February 2006 297 Biol. Pharm. Bull. 29(2) 297—301 (2006)