G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche
Ziru Li, Julie Hardij, Simon S. Evers, Chelsea R. Hutch, Sarah M. Choi, Yikai Shao, Brian S. Learman, Kenneth T. Lewis, Rebecca L. Schill, Hiroyuki Mori, Devika P. Bagchi, Steven M. Romanelli, Ki-Suk Kim, Emily Bowers, Cameron Griffin, Randy J. Seeley, Kanakadurga Singer, Darleen A. Sandoval, Clifford J. Rosen, Ormond A. MacDougald
Ziru Li, Julie Hardij, Simon S. Evers, Chelsea R. Hutch, Sarah M. Choi, Yikai Shao, Brian S. Learman, Kenneth T. Lewis, Rebecca L. Schill, Hiroyuki Mori, Devika P. Bagchi, Steven M. Romanelli, Ki-Suk Kim, Emily Bowers, Cameron Griffin, Randy J. Seeley, Kanakadurga Singer, Darleen A. Sandoval, Clifford J. Rosen, Ormond A. MacDougald
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Research Article Bone biology Endocrinology

G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche

Abstract

Bariatric surgeries are integral to the management of obesity and its metabolic complications. However, these surgeries cause bone loss and increase fracture risk through poorly understood mechanisms. In a mouse model, vertical sleeve gastrectomy (VSG) caused trabecular and cortical bone loss that was independent of sex, body weight, and diet, and this loss was characterized by impaired osteoid mineralization and bone formation. VSG had a profound effect on the bone marrow niche, with rapid loss of marrow adipose tissue, and expansion of myeloid cellularity, leading to increased circulating neutrophils. Following VSG, circulating granulocyte–colony stimulating factor (G-CSF) was increased in mice, and was transiently elevated in a longitudinal study of humans. Elevation of G-CSF was found to recapitulate many effects of VSG on bone and the marrow niche. In addition to stimulatory effects of G-CSF on myelopoiesis, endogenous G-CSF suppressed development of marrow adipocytes and hindered accrual of peak cortical and trabecular bone. Effects of VSG on induction of neutrophils and depletion of marrow adiposity were reduced in mice deficient for G-CSF; however, bone mass was not influenced. Although not a primary mechanism for bone loss with VSG, G-CSF plays an intermediary role for effects of VSG on the bone marrow niche.

Authors

Ziru Li, Julie Hardij, Simon S. Evers, Chelsea R. Hutch, Sarah M. Choi, Yikai Shao, Brian S. Learman, Kenneth T. Lewis, Rebecca L. Schill, Hiroyuki Mori, Devika P. Bagchi, Steven M. Romanelli, Ki-Suk Kim, Emily Bowers, Cameron Griffin, Randy J. Seeley, Kanakadurga Singer, Darleen A. Sandoval, Clifford J. Rosen, Ormond A. MacDougald

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Figure 5

VSG in mice and humans rapidly increases circulating G-CSF, which in mice is sufficient to cause loss of bone and BMAT.

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VSG in mice and humans rapidly increases circulating G-CSF, which in mic...
(A) Circulating G-CSF levels in male C57BL/6J mice were measured at 1, 2, 4, and 8 weeks (right panel) after sham or VSG surgery (Sham, n = 5 and VSG, n = 9 at 1 week; Sham, n = 5 and VSG, n = 11 at 2 weeks; Sham, n = 7 and VSG, n = 12 at 4 weeks; Sham, n = 10 and VSG, n = 16 at 8 weeks). (B) Female young patients underwent VSG surgery. Circulating G-CSF concentrations before (n = 22) and at 1 (n = 22), 3 (n = 17), 6 (n = 12), and 12 (n = 4) months after surgery. (C–G) C3H/HeJ mice at 12 weeks of age were implanted with osmotic minipumps containing saline (–) or recombinant murine G-CSF (+) (3 μg/mouse). Animals were sacrificed 4 weeks after implantation (n = 5 for each group). (C) Circulating G-CSF concentrations at 4 weeks. (D) Tibial trabecular characteristics including Tb. BV/TV, Tb. BMD, Tb. N, and Tb. Sp. The inverse correlation between Tb. BV/TV and circulating G-CSF concentrations is shown. (E) Ct. BA/TA and Ct. Th were measured. Linear regression reveals the inverse correlation between Ct. BA/TA and circulating G-CSF concentrations. (F) Proximal and distal tibial BMAT volume was determined by osmium staining and μCT. (G) Representative H&E-stained sections from proximal and distal tibiae with ×200 magnification are shown. Scale bars, 100 μm. *Statistical difference for indicated comparisons at P < 0.05 by 2-way ANOVA with Sidak’s multiple comparisons test (A), Wilcoxon matched-pair signed rank test (B), and 2-sample t test (C–F). P values across C to F were adjusted for multiple testing using limma package in R with FDR method.