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. 2025 Mar 17;26(6):2704.
doi: 10.3390/ijms26062704.

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

Parichart Toejing  1 , Ohnmar Myint  1 , Asada Leelahavanichkul  2 , Somyoth Sridurongrit  3 , Matthew B Greenblatt  4   5 , Sutada Lotinun  1
Affiliations

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

Parichart Toejing et al. Int J Mol Sci. .

Abstract

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 TGF-β signaling on bone remodeling during CKD have not been investigated. Here, we determined the effects of TGF-β receptor I (TβRI) overexpression under the control of Mx1-Cre on bone remodeling in CKD mice (Mx1;TβRICA-CKD mice). Our results demonstrated that kidney fibrosis and serum urea nitrogen levels were elevated in Mx1;TβRICA-CKD mice compared to WT-CKD, indicating that TβRI overexpression exacerbated renal injury during CKD. Serum calcium was decreased, while PTH was enhanced, in Mx1;TβRICA-CKD mice. Mx1;TβRICA-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 Mx1;TβRICA-CKD. Likewise, mRNA expression levels of an osteoclastogenesis marker, Tnfsf11/Tnfrsf11b, was increased, and osteoblast marker genes Runx2 and Sp7 were decreased in Mx1;TβRICA-CKD mice. Mx1;TβRICA-CKD mice displayed increased inflammatory cytokines levels. Together, our results indicated that in the setting of CKD, TβRI 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.

Keywords: TGFβ; bone; chronic kidney disease; osteoblast; osteoclast.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Serum chemistries in experimental groups. Serum levels of (A) urea nitrogen (n = 5–6), (B) creatinine (n = 4), (C) phosphorus (n = 5–7) and (D) calcium (n = 4–5). Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA.
Figure 1
Figure 1
Serum chemistries in experimental groups. Serum levels of (A) urea nitrogen (n = 5–6), (B) creatinine (n = 4), (C) phosphorus (n = 5–7) and (D) calcium (n = 4–5). Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA.
Figure 2
Figure 2
Mx1;TβRICA-CKD mice show induced renal fibrosis. (A) Masson’s trichrome staining of kidneys. Blue color indicates fibrosis with accumulation of collagen. Scale bar = 100 μm. (B) IFTA score in kidneys (n = 5). Results are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA.
Figure 3
Figure 3
Serum PTH is increased in Mx1;TβRICA-CKD mice. Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA (n = 4).
Figure 4
Figure 4
Overexpression of TβRI increases femoral bone loss in CKD mice. (A) Representative μCT images of cancellous and cortical bone in femurs. (B) μCT analysis of femoral cancellous bone (n = 4–5). (C) μCT analysis of femoral cortical bone (n = 4–5). Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA (n = 4–7).
Figure 4
Figure 4
Overexpression of TβRI increases femoral bone loss in CKD mice. (A) Representative μCT images of cancellous and cortical bone in femurs. (B) μCT analysis of femoral cancellous bone (n = 4–5). (C) μCT analysis of femoral cortical bone (n = 4–5). Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA (n = 4–7).
Figure 5
Figure 5
Overexpression of TβRI increases mandibular bone loss in CKD mice. (A) Representative μCT images of cancellous and cortical bone in mandibles. (B) μCT analysis of mandibular cancellous bone (n = 5–6). (C) μCT analysis of mandibular cortical bone (n = 5). Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA (n = 4–7).
Figure 5
Figure 5
Overexpression of TβRI increases mandibular bone loss in CKD mice. (A) Representative μCT images of cancellous and cortical bone in mandibles. (B) μCT analysis of mandibular cancellous bone (n = 5–6). (C) μCT analysis of mandibular cortical bone (n = 5). Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA (n = 4–7).
Figure 6
Figure 6
Tibial bone histomorphometric data of experimental groups (n = 4–7). Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA (n = 4–7).
Figure 7
Figure 7
Constitutive TβRI activation decreases osteoblast and increases osteoclast-related gene expression in femurs of CKD mice. Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA (n = 3–4).
Figure 8
Figure 8
Mx1;TβRICA-CKD mice had increased inflammatory cytokines. Serum levels of TNF-α, IL-6, IL-23, IL-1α, IL-10 and IFN-β (n = 3–7). Data are mean ± SEM. a p < 0.05 compared to WT, b p < 0.05 compared to WT-CKD, and c p < 0.05 compared to Mx1;TβRICA.
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