Targeting osteoblast fatty acid metabolism attenuates skeletal and cardiovascular complications in chronic kidney disease models

Petra Simic; Han Xie; Wen Zhou; Yu Fan; Renata C. Pereira; Fangcong Dong; Jason D. Roh; Isidro B. Salusky; Charandeep Singh; Russell P. Goodman; Ashok Khatri; Eugene P. Rhee

doi:10.1172/JCI207322

¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

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¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

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¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

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¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

Find articles by Fan, Y. in: PubMed | Google Scholar

¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

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¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

Find articles by Dong, F. in: PubMed | Google Scholar

¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

Find articles by Roh, J. in: PubMed | Google Scholar

¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

Find articles by Salusky, I. in: PubMed | Google Scholar

¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

Find articles by Singh, C. in: PubMed | Google Scholar

¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

Find articles by Goodman, R. in: PubMed | Google Scholar

¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

Find articles by Khatri, A. in: PubMed | Google Scholar

¹Division of Nephrology and Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

²Department of Pediatrics, Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

³Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁴Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Department of Pediatrics, Division of Pediatric Nephrology, David GeffenSchool of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, United States of America

⁷Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

Find articles by Rhee, E. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI207322.
Copyright © 2026, Simic et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published September 29, 2026 - Version history

Chronic kidney disease (CKD) disrupts mineral homeostasis, leading to impaired skeletal mineralization and cardiovascular pathology, yet the mechanism linking these processes remains undefined. Here we identify glycerol-3-phosphate acyltransferase 2 (GPAT2) as a regulator that couples free fatty acid (FFA) partitioning in osteoblasts to systemic phosphate balance. In mouse and human CKD, elevated osteoblast GPAT2 routes FFA away from mitochondrial oxidation, limiting phosphate incorporation into bone, and toward lysophosphatidic acid synthesis, increasing production of the phosphaturic hormone fibroblast growth factor 23 (FGF23). By contrast, osteoblast-specific Gpat2 deletion restores osteoblast FFA oxidation and skeletal phosphate incorporation, lowers circulating phosphate and FGF23, and attenuates vascular calcification and cardiac hypertrophy in CKD. Further, a bone-targeted GPAT inhibitor recapitulates most of these beneficial effects. These findings establish a fundamental role for osteoblast lipid metabolism in mineral homeostasis and identify GPAT2 in bone as a promising therapeutic target for both skeletal and cardiovascular complications of CKD.

Targeting osteoblast fatty acid metabolism attenuates skeletal and cardiovascular complications in chronic kidney disease models

Petra Simic,¹ Han Xie,¹ Wen Zhou,¹ Yu Fan,¹ Renata C. Pereira,² Fangcong Dong,³ Jason D. Roh,⁴ Isidro B. Salusky,⁵ Charandeep Singh,⁶ Russell P. Goodman,⁷ Ashok Khatri,⁷ and Eugene P. Rhee¹

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Targeting osteoblast fatty acid metabolism attenuates skeletal and cardiovascular complications in chronic kidney disease models

Petra Simic,1 Han Xie,1 Wen Zhou,1 Yu Fan,1 Renata C. Pereira,2 Fangcong Dong,3 Jason D. Roh,4 Isidro B. Salusky,5 Charandeep Singh,6 Russell P. Goodman,7 Ashok Khatri,7 and Eugene P. Rhee1

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Petra Simic,¹ Han Xie,¹ Wen Zhou,¹ Yu Fan,¹ Renata C. Pereira,² Fangcong Dong,³ Jason D. Roh,⁴ Isidro B. Salusky,⁵ Charandeep Singh,⁶ Russell P. Goodman,⁷ Ashok Khatri,⁷ and Eugene P. Rhee¹