Abstract: TH-OR033
Indoxyl Sulfate Disrupts Mitochondrial Metabolic Adaptation During Osteoblast Differentiation in CKD
Session Information
- Bone and Mineral Metabolism: Emerging Mechanisms and Disease
October 22, 2026 | Location: Room 405, Convention Center
Abstract Time: 05:20 PM - 05:30 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Wang, Zuoyu, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Dai, Chunsun, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiang, Lei, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background
Low-turnover bone disease develops early during chronic kidney disease (CKD), even before overt abnormalities in mineral metabolism become apparent. Indoxyl sulfate (IS), a protein-bound uremic toxin that accumulates in early CKD, has been implicated in osteoblast dysfunction. However, the effects of IS on metabolic adaptation during osteoblast differentiation remain incompletely understood.
Methods
Metabolomic datasets from CKD cohorts were analyzed to assess circulating IS levels across CKD stages. Bone histomorphometry and DXA data from CKD patients were reviewed to evaluate bone volume abnormalities. A unilateral nephrectomy mouse model with chronic IS exposure was established and analyzed by micro-CT and dynamic histomorphometry. Primary osteoblasts were exposed to IS during osteogenic differentiation to assess function, glycolytic metabolism, mitochondrial morphology, and signaling using ALP/Alizarin Red staining, Seahorse analysis, immunoblotting, immunofluorescence, and transcriptomics. Molidustat was used to assess HIF-1α contribution to IS-induced metabolic dysfunction.
Results
Serum IS increased progressively with declining eGFR and was elevated in early CKD. Among 29 CKD patients, 62.1% exhibited reduced BV/TV and low femoral neck BMD. Chronic IS exposure reduced BMD, trabecular bone volume/thickness, and bone formation rate in nephrectomized mice. In vitro, IS suppressed osteoblast proliferation, ALP activity, mineralization, and RUNX2/Osterix expression. Transcriptomics revealed activation of AhR-responsive pathways with altered metabolic programs. Seahorse analysis showed that osteoblast differentiation required increased glycolytic activity, which was markedly impaired by IS along with reduced HIF-1α expression. IS also induced mitochondrial elongation with increased OPA1, reduced OMA1, and altered mitochondrial biogenesis signaling. Molidustat partially restored glycolytic activity, osteoblast differentiation, and mineralization after IS exposure.
Conclusion
IS impairs osteoblast differentiation and bone formation by disrupting glycolytic reprogramming and mitochondrial dynamics. Restoring HIF-1α signaling partially attenuates IS-induced osteoblast dysfunction, suggesting that metabolic adaptation contributes to early CKD-associated low-turnover bone disease.
Funding
- Government Support – Non-U.S.