Krieger Nancy S, Chen Luojing, Becker Jennifer, DeBoyace Sean, Wang Hongwei, Favus Murray J, Bushinsky David A
Division of Nephrology University of Rochester School of Medicine Rochester NY USA.
Section of Endocrinology University of Chicago Pritzker School of Medicine Chicago IL USA.
JBMR Plus. 2020 Feb 25;4(4):e10350. doi: 10.1002/jbm4.10350. eCollection 2020 Apr.
To study human idiopathic hypercalciuria (IH), we developed an animal model, genetic hypercalciuric stone-forming (GHS) rats, whose pathophysiology parallels that in IH. All GHS rats form kidney stones and have decreased BMD and bone quality compared with the founder Sprague-Dawley (SD) rats. To understand the bone defect, we characterized osteoclast and osteoblast activity in the GHS compared with SD rats. Bone marrow cells were isolated from femurs of GHS and SD rats and cultured to optimize differentiation into osteoclasts or osteoblasts. Osteoclasts were stained for TRAcP (tartrate resistant acid phosphatase), cultured to assess resorptive activity, and analyzed for specific gene expression. Marrow stromal cells or primary neonatal calvarial cells were differentiated to osteoblasts, and osteoblastic gene expression as well as mineralization was analyzed. There was increased osteoclastogenesis and increased resorption pit formation in GHS compared with SD cultures. Osteoclasts had increased expression of , , and in cells from GHS compared with SD rats. Osteoblastic gene expression and mineralization was significantly decreased. Thus, alterations in baseline activity of both osteoclasts and osteoblasts in GHS rats, led to decreased BMD and bone quality, perhaps because of their known increase in vitamin D receptors. Better understanding of the role of GHS bone cells in decreased BMD and quality may provide new strategies to mitigate the low BMD and increased fracture risk found in patients with IH. © 2020 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
为了研究人类特发性高钙尿症（IH），我们建立了一种动物模型——遗传性高钙尿结石形成（GHS）大鼠，其病理生理学与IH相似。与亲代斯普拉格-道利（SD）大鼠相比，所有GHS大鼠都会形成肾结石，且骨密度和骨质量降低。为了解骨缺陷情况，我们对GHS大鼠与SD大鼠的破骨细胞和成骨细胞活性进行了表征。从GHS大鼠和SD大鼠的股骨中分离出骨髓细胞，并进行培养以优化其向破骨细胞或成骨细胞的分化。对破骨细胞进行抗酒石酸酸性磷酸酶（TRAcP）染色，培养以评估其吸收活性，并分析其特定基因表达。将骨髓基质细胞或原代新生颅骨细胞分化为成骨细胞，并分析成骨细胞基因表达以及矿化情况。与SD培养物相比，GHS培养物中的破骨细胞生成增加，吸收凹坑形成增多。与SD大鼠相比，GHS大鼠细胞中的破骨细胞、 和 的表达增加。成骨细胞基因表达和矿化显著降低。因此，GHS大鼠破骨细胞和成骨细胞基线活性的改变导致了骨密度和骨质量降低，这可能是由于它们已知增加的维生素D受体所致。更好地了解GHS骨细胞在骨密度降低和质量下降中的作用，可能会为减轻IH患者中发现的低骨密度和骨折风险增加提供新策略。© 2020作者。由Wiley Periodicals, Inc.代表美国骨与矿物质研究学会出版。
