Effects of the bisphosphonate risedronate on osteopenia in OASIS-deficient mice

Endoplasmic reticulum (ER) stress has been reported to be linked to various diseases such as diabetes, neurodegenerative diseases, and osteogenesis imperfecta (OI). Old astrocyte specifically induced substance (OASIS), a novel type of ER stress transducer, is a basic leucine zipper transcription factor belonging to the CREB/ATF family and is markedly expressed in osteoblasts. Recently, we demonstrated that OASIS activates the transcription of the gene for type I collagen, Col1a1, and contributes to the secretion of bone matrix proteins in osteoblasts. OASIS-/- mice exhibit severe osteopenia involving a decrease in type I collagen in the bone matrix and a dysfunction of osteoblasts, which show abnormal expansion of the rough ER. These phenotypic features of osteopenia are similar to those observed in OI type I. In this study, we investigated whether administration of the third-generation bisphosphonate risedronate (RIS) is effective for treating osteopenia in OASIS-/- mice. Histological and histomorphometric analyses revealed that the trabecular bones increased dramatically in OASIS-/- mice treated with RIS, owing to the inhibition of bone resorption. Intriguingly, the abnormal expansion of the rough ER in OASIS-/- osteoblasts was improved by the treatment with RIS. Taken together, we conclude that OASIS-/- mice will be useful as new model mice for evaluating the medicinal effects of osteopenia treatments and developing new drugs for the osteopenia associated with diseases such as OI and osteoporosis.