Nephrectomy Induces Severe Bone Loss in Mice Expressing Constitutively Active TGFβ Receptor Type I

Transforming growth factor beta (TGF-β), a master regulator of renal fibrosis, is the hallmark of chronic kidney disease (CKD) progression, and CKD worsens bone remodeling. However, the effects of the dysregulation of <i>TGF-β</i> signaling on bone remodeling during CKD have not been investigated. Here, we determined the effects of TGF-β receptor I (<i>TβRI</i>) overexpression under the control of Mx1-Cre on bone remodeling in CKD mice (<i>Mx1;TβRI^CA</i>-CKD mice). Our results demonstrated that kidney fibrosis and serum urea nitrogen levels were elevated in <i>Mx1;TβRI^CA</i>-CKD mice compared to WT-CKD, indicating that <i>TβRI</i> overexpression exacerbated renal injury during CKD. Serum calcium was decreased, while PTH was enhanced, in <i>Mx1;TβRI^CA</i>-CKD mice. <i>Mx1;TβRI^CA</i>-CKD mice displayed severe osteopenia as assessed by uCT in both femurs and mandibles. An histomorphometric analysis showed that tibial cancellous bone volume was decreased in <i>Mx1;TβRI^CA</i>-CKD. Likewise, mRNA expression levels of an osteoclastogenesis marker, <i>Tnfsf11/Tnfrsf11b,</i> was increased, and osteoblast marker genes <i>Runx2</i> and <i>Sp7</i> were decreased in <i>Mx1;TβRI^CA</i>-CKD mice. <i>Mx1;TβRI^CA</i>-CKD mice displayed increased inflammatory cytokines levels. Together, our results indicated that in the setting of CKD, <i>TβRI</i> overexpression induced both CKD progression and the dysregulation of bone remodeling, leading to severe bone loss. As such, these data provide an avenue for the future development of therapeutics for CKD-induced osteoporosis.