{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:46:46Z","timestamp":1787028406987,"version":"build-2736575974"},"reference-count":146,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T00:00:00Z","timestamp":1534982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK070790 and DK089137 (K.A.H.)"],"award-info":[{"award-number":["DK070790 and DK089137 (K.A.H.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteopenia\/osteoporosis resulting from the skeletal component of the CKD-MBD, renal osteodystrophy (ROD), in patients with CKD exceeds that of the general population and is a major public health concern. That CKD is associated with compromised bone health is widely accepted, yet the mechanisms underlying impaired bone metabolism in CKD are not fully understood. Therefore, clarification of the molecular mechanisms by which CKD produces ROD is of crucial significance. We have shown that activin A, a member of the transforming growth factor (TGF)-\u03b2 super family, is an important positive regulator of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis with Smad-mediated signaling being crucial for inducing osteoclast development and function. Recently, we have demonstrated systemic activation of activin receptors and activin A levels in CKD mouse models, such as diabetic CKD and Alport (AL) syndrome. In these CKD mouse models, bone remodeling caused by increased osteoclast numbers and activated osteoclastic bone resorption was observed and treatment with an activin receptor ligand trap repaired CKD-induced-osteoclastic bone resorption and stimulated individual osteoblastic bone formation, irrespective of parathyroid hormone (PTH) elevation. These findings have opened a new field for exploring mechanisms of activin A-enhanced osteoclast formation and function in CKD. Activin A appears to be a strong candidate for CKD-induced high-turnover ROD. Therefore, the treatment with the decoy receptor for activin A might be a good candidate for treatment for CKD-induced osteopenia or osteoporosis, indicating that the new findings from in these studies will lead to the identification of novel therapeutic targets for CKD-related and osteopenia and osteoporosis in general. In this review, we describe the impact of CKD-induced Smad signaling in osteoclasts, osteoblasts and vascular cells in CKD.<\/jats:p>","DOI":"10.3390\/ijms19092490","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T03:00:46Z","timestamp":1534993246000},"page":"2490","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder"],"prefix":"10.3390","volume":"19","author":[{"given":"Toshifumi","family":"Sugatani","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/321776a0","article-title":"Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid","volume":"321","author":"Vale","year":"1986","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1097\/00006254-198702000-00015","article-title":"Pituitary FSH is released by a heterodimer of the \u03b2 subunits from the two forms of inhibin","volume":"42","author":"Ling","year":"1987","journal-title":"Obstet. Gynecol. 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