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Glucose- and glutamine-dependent bioenergetics sensitize bone mechanoresponse after unloading by modulating osteocyte calcium dynamics
Xiyu Liu, … , Liangliang Shen, Da Jing
Xiyu Liu, … , Liangliang Shen, Da Jing
Published December 13, 2022
Citation Information: J Clin Invest. 2023;133(3):e164508. https://doi.org/10.1172/JCI164508.
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Research Article Bone biology

Glucose- and glutamine-dependent bioenergetics sensitize bone mechanoresponse after unloading by modulating osteocyte calcium dynamics

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Abstract

Disuse osteoporosis is a metabolic bone disease resulting from skeletal unloading (e.g., during extended bed rest, limb immobilization, and spaceflight), and the slow and insufficient bone recovery during reambulation remains an unresolved medical challenge. Here, we demonstrated that loading-induced increase in bone architecture/strength was suppressed in skeletons previously exposed to unloading. This reduction in bone mechanosensitivity was directly associated with attenuated osteocytic Ca2+ oscillatory dynamics. The unloading-induced compromised osteocytic Ca2+ response to reloading resulted from the HIF-1α/PDK1 axis–mediated increase in glycolysis, and a subsequent reduction in ATP synthesis. HIF-1α also transcriptionally induced substantial glutaminase 2 expression and thereby glutamine addiction in osteocytes. Inhibition of glycolysis by blockade of PDK1 or glutamine supplementation restored the mechanosensitivity in those skeletons with previous unloading by fueling the tricarboxylic acid cycle and rescuing subsequent Ca2+ oscillations in osteocytes. Thus, we provide mechanistic insight into disuse-induced deterioration of bone mechanosensitivity and a promising therapeutic approach to accelerate bone recovery after long-duration disuse.

Authors

Xiyu Liu, Zedong Yan, Jing Cai, Dan Wang, Yongqing Yang, Yuanjun Ding, Xi Shao, Xiaoxia Hao, Erping Luo, X. Edward Guo, Peng Luo, Liangliang Shen, Da Jing

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Figure 7

Glutamine supplementation enhances bone mechanosensitivity to reloading in mice previously exposed to HU via osteocyte-mediated regulation of osteoblasts and osteoclasts.

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Glutamine supplementation enhances bone mechanosensitivity to reloading ...
(A) Experimental protocol of 4-week tail suspension to establish the HU model, subsequent glutamine supplementation (daily injection at 673 mg/kg body weight via tail vein for 1 week), and mechanical reloading with uniaxial cyclic compression (1,200 cycles/day for 2 weeks) in mice. (B and C) Representative micro-CT images showing proximal tibial trabecular bone architecture and cortical bone thickness, and the corresponding quantitative data. n = 6 per group. (D) Three-point bending tests for assessing whole-bone mechanical properties. n = 6 per group. (E) Dynamic bone histomorphometry using calcein and alizarin red double labeling. n = 6 per group. (F) Schematic representation of conditioned medium collection from SMG-exposed MLO-Y4 cells treated with or without glutamine in response to FSS stimulation (2 Pa for 3 hours), and its incubation in SMG-exposed primary osteoblasts and RAW264.7 osteoclast precursor cells. (G–I) Survival and differentiation assays of SMG-exposed primary osteoblasts treated with conditioned medium collected from SMG-exposed MLO-Y4 osteocytic cells with glutamine supplementation in response to FSS stimulation. (G) Western blotting assays of protein expression of Col1a1, Runx2, and Osx in primary osteoblasts. (H and I) ALP activity, ALP staining, and alizarin red staining assays in primary osteoblasts. n = 6 per group. (J and K) Osteoclastogenesis assays in SMG-exposed RAW264.7 cells (pre-osteoclasts) treated with conditioned medium collected from SMG-exposed MLO-Y4 cells with glutamine supplementation in response to FSS stimulation. (J) TRAP staining to quantify the formation of osteoclasts. n = 6 per group. (K) Western blotting analyses of the expression of osteoclast-related markers in RAW264.7 cells, including TRAP, cathepsin K, NFATc1, and calcitonin receptor. Graphs represent mean ± SD. **P < 0.01, ***P < 0.001 by 2-way ANOVA with Bonferroni’s post-test. Scale bars: E, 30 μm; I and J, 50 μm.

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