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Nephrectomy Induces Severe Bone Loss in Mice Expressing Constitutively Active TGFβ Receptor Type I
Parichart Toejing1, Ohnmar Myint1, Asada Leelahavanichkul2
1Center of Excellence in Skeletal Disorders and Enzyme Reaction Mechanism, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.
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.
Insights
Overexpression of TGF-β receptor I in chronic kidney disease (CKD) mice worsened kidney injury and bone loss. This study reveals TGF-β signaling dysregulation
Area of Science:
- Nephrology
- Endocrinology
- Bone Biology
Background:
- Transforming growth factor beta (TGF-β) is a key regulator of renal fibrosis and chronic kidney disease (CKD) progression.
- CKD is known to negatively impact bone remodeling, but the specific role of TGF-β signaling dysregulation in this process remains unclear.
Purpose of the Study:
- To investigate the effects of TGF-β receptor I (TβRI) overexpression on bone remodeling in the context of CKD.
- To determine if TβRI overexpression exacerbates renal injury and bone loss in a mouse model of CKD.
Main Methods:
- Utilized a mouse model with TβRI overexpression controlled by Mx1-Cre (Mx1;TβRI-CKD mice) to study CKD and bone remodeling.
- Assessed renal injury through serum urea nitrogen levels and kidney fibrosis.
- Evaluated bone parameters using micro-computed tomography (μCT) and histomorphometry, alongside gene expression analysis of bone remodeling markers and inflammatory cytokines.
Main Results:
- Mx1;TβRI-CKD mice exhibited exacerbated kidney fibrosis and elevated serum urea nitrogen compared to wild-type CKD controls.
- These mice showed decreased serum calcium, enhanced parathyroid hormone (PTH), and severe osteopenia in femurs and mandibles.
- Histomorphometry revealed reduced tibial cancellous bone volume, increased osteoclastogenesis markers, and decreased osteoblast marker gene expression.
Conclusions:
- TβRI overexpression in CKD mice exacerbates renal injury and leads to significant dysregulation of bone remodeling, resulting in severe bone loss.
- The findings highlight the detrimental role of TGF-β signaling in CKD-induced osteoporosis.
- This research provides a foundation for developing targeted therapies for osteoporosis associated with chronic kidney disease.
