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 4

Bone mass after VSG is inversely correlated with myeloid cell expansion.

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Bone mass after VSG is inversely correlated with myeloid cell expansion....
Male mice at 4 weeks of age were fed a 60% HFD for 8 weeks and then received either sham or VSG surgery. Mice remained on a HFD until euthanasia 8 weeks after surgery. (A) Wright-Giemsa staining was performed on a femoral bone marrow touch preparation. Representative pictures at ×1000 magnification are shown. Scale bars, 20 μm. Yellow arrows show neutrophils and their myeloid precursors; red arrows show erythroid cells. (B) Blind counting of myeloid and erythroid cells was performed by a board-certified pathologist. Linear regression on the relationship between myeloid/erythroid cell ratio and Ct. BA/TA was performed (n = 15 for Sham and n = 10 for VSG). (C) Circulating proportion of neutrophils versus total white blood cells (WBCs) was calculated after performing a CBC. Linear correlations between neutrophil proportion and Tb. BV/TV or Ct. BA/TA are shown (n = 20 for Sham and n = 22 for VSG). (D) Hematocrit was calculated from the CBC. Linear regression demonstrates the positive correlation between hematocrit and Tb. BV/TV (n = 28 for Sham and n = 14 for VSG). *Statistical difference for indicated comparisons at P < 0.05 by 2-sample t test (B–D).