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 3

Loss of bone after VSG is due to decreased bone formation and impaired mineralization.

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Loss of bone after VSG is due to decreased bone formation and impaired m...
Male mice on a NCD received either sham or VSG surgery at 12 weeks of age and were euthanized 2 weeks later. Mice were intraperitoneally injected with calcein (20 mg/kg) 9 and 2 days prior to euthanasia. (A) Tibial bone surface (BS) and osteoblast number (Ob. N) were determined on H&E-stained decalcified sections and calculated by Bioquant software. Tibial osteoclast surface (Oc. S) was determined from decalcified TRAP-stained sections and normalized by bone surface (n = 9 for each group). (B) Undecalcified femurs were embedded in plastic, sectioned, and stained with Masson Trichrome to calculate osteoid surface (S)/bone surface (BS) and osteoid width. Arrows indicate the borders of osteoid surface (n = 10 for Sham and n = 11 for VSG). (C) Calcein-labeled mineralized femurs were sectioned and fluorescence was visualized. Distance between calcein incorporation into mineralized matrix is shown by arrows. (D) Analyses of fluorescent double-labeled surface was used to calculate bone formation rate, mineral apposition rate, and osteoid maturation time using Bioquant software (n = 10 for Sham and n = 11 for VSG). (E) Expression of Sp7, Alpl, and Bglap mRNAs from whole femur tissue was analyzed by qPCR and normalized by the expression of the geometric mean of housekeeping genes Hprt, Rpl32A, and Tbp (n = 5 for Sham and n = 9 for VSG at 1 week; n = 5 for Sham and n = 12 for VSG at 2 weeks). *Statistical difference for indicated comparisons at P < 0.05 by 2-sample t test (A, B, and D) and 2-way ANOVA with Sidak’s multiple comparisons test (E). P values across A to D were adjusted for multiple testing using limma package in R with FDR method.