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Pharmacologic or genetic interference with atrogene signaling protects against glucocorticoid-induced musculoskeletal and cardiac disease
Amy Y. Sato, … , Tamara Alliston, Teresita Bellido
Amy Y. Sato, … , Tamara Alliston, Teresita Bellido
Published October 15, 2024
Citation Information: JCI Insight. 2024;9(21):e182664. https://doi.org/10.1172/jci.insight.182664.
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Research Article Bone biology Article has an altmetric score of 4

Pharmacologic or genetic interference with atrogene signaling protects against glucocorticoid-induced musculoskeletal and cardiac disease

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Abstract

Despite their beneficial actions as immunosuppressants, glucocorticoids (GC) have devastating effects on the musculoskeletal and cardiac systems, as long-term treated patients exhibit high incidence of falls, bone fractures, and cardiovascular events. Herein, we show that GC upregulate simultaneously in bone, skeletal muscle, and the heart the expression of E3 ubiquitin ligases (atrogenes), known to stimulate the proteasomal degradation of proteins. Activation of vitamin D receptor (VDR) signaling with the VDR ligands calcitriol or eldecalcitol prevented GC-induced atrogene upregulation in vivo and ex vivo in bone/muscle organ cultures and preserved tissue structure/mass and function of the 3 tissues in vivo. Direct pharmacologic inhibition of the proteasome with carfilzomib also conferred musculoskeletal protection. Genetic loss of the atrogene MuRF1-mediated protein ubiquitination in ΔRING mice afforded temporary or sustained protection from GC excess in bone or skeletal and heart muscle. We concluded that the atrogene pathway downstream of MuRF1 underlies GC action in bone, muscle, and the heart, and it can be pharmacologically or genetically targeted to confer protection against the damaging actions of GC simultaneously in the 3 tissues.

Authors

Amy Y. Sato, Meloney Cregor, Kevin McAndrews, Charles A. Schurman, Eric Schaible, Jennifer Shutter, Punit Vyas, Bhawana Adhikari, Monte S. Willis, Marjan Boerma, Tamara Alliston, Teresita Bellido

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Figure 3

VDR ligands prevent GC adverse actions on bone mechanical properties, fully and partially, at the tissue and collagen fibril level, respectively.

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VDR ligands prevent GC adverse actions on bone mechanical properties, fu...
Mice were implanted with 2.1 mg/kg/d prednisolone or placebo slow-release pellets and gavaged with 50 ng/kg/d 1,25D3, ED, or vehicle 5 times per week for 8 weeks. (A) Structural and (B) material properties of bone, as assessed by 3-point bending of femurs. MPa, megapascal. n = 10–12. (C) Images for sample preparation for tensile testing utilized in synchrotron small-angle x-ray scattering (SAXS) analyses. (D) Ultimate and yield strain, as assessed by SAXS strain vs. stress curve analysis of combined ulnae and radii bones undergoing uniaxial tension testing. (E) Tissue strain was time matched to collagen strains (SAXS strain vs. strain curve analysis) at yield and maximum stress for comparisons of stress-carrying components with bone during deformation. n = 7–12. *P < 0.05 vs. corresponding placebo treated, #P < 0.05 vs. corresponding vehicle treated, ^P < 0.05 vs. corresponding 1,25D3 treated by 2-way ANOVA, Tukey’s post hoc test, ΩP < 0.05 vs. placebo and vehicle-treated controls by 1-way ANOVA, Dunnett’s method post hoc test.

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