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1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites
Samiksha Wasnik, … , Kin-Hing William Lau, Xiaolei Tang
Samiksha Wasnik, … , Kin-Hing William Lau, Xiaolei Tang
Published September 6, 2018
Citation Information: JCI Insight. 2018;3(17):e98773. https://doi.org/10.1172/jci.insight.98773.
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Research Article Bone biology

1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites

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Abstract

An indispensable role of macrophages in bone repair has been well recognized. Previous data have demonstrated the copresence of M1 macrophages and mesenchymal stem cells (MSCs) during the proinflammatory stage of bone repair. However, the exact role of M1 macrophages in MSC function and bone repair is unknown. This study aimed to define the role of M1 macrophages at bone injury sites via the function of 1,25-Dihydroxyvitamin D (1,25[OH]2D) in suppressing M1 but promoting M2 differentiation. We showed that 1,25(OH)2D suppressed M1 macrophage–mediated enhancement of MSC migration. Additionally, 1,25(OH)2D inhibited M1 macrophage secretion of osteogenic proteins (i.e., Oncostatin M, TNF-α, and IL-6). Importantly, the 1,25(OH)2D-mediated suppression of osteogenic function in M1 macrophages at the proinflammatory stage was associated with 1,25(OH)2D-mediated reduction of MSC abundance, compromised osteogenic potential of MSCs, and impairment of fracture repair. Furthermore, outside the proinflammatory stage, 1,25(OH)2D treatment did not suppress fracture repair. Accordingly, our data support 2 conclusions: (a) M1 macrophages are important for the recruitment and osteogenic priming of MSCs and, hence, are necessary for fracture repair, and (b) under vitamin D–sufficient conditions, 1,25(OH)2D treatment is unnecessary and can be detrimental if provided during the proinflammatory stage of fracture healing.

Authors

Samiksha Wasnik, Charles H. Rundle, David J. Baylink, Mohammad Safaie Yazdi, Edmundo E. Carreon, Yi Xu, Xuezhong Qin, Kin-Hing William Lau, Xiaolei Tang

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Figure 7

Local s.c. treatment with 1,25(OH)2D during the proinflammatory stage compromised the osteogenic potential of MSCs at fracture sites.

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Local s.c. treatment with 1,25(OH)2D during the proinflammatory stage co...
(A) B6 mice were subjected to fracture surgery (Fx). Immediately after the fracture surgery, the animals received a daily s.c. dose of either vehicle control (VC) or 100 ng/kg/mouse 1,25(OH)2D (VD) at fracture sites. At days 1 and 4, intact (intact bones) and fractured (Fx bones) bones were examined for the mRNA expression of runx2, osterix (OSX), and osteocalcin (OCN) by qPCR. (B) B6 mice were subjected to fracture surgery. Immediately after the fracture surgery, the animals received a daily s.c. dose of VC, 100 ng/kg/mouse 1,25(OH)2D (VD), or 1,000 ng/kg/mouse 1,25(OH)2D (VD). At day 4, intact and fractured bones were collected for isolating CD45– mesenchyme cells. The purified cells were cultured in an MSC medium. Upon reaching 70%–80% confluence, an equal number of the cells were used for the in vitro bone nodule assay. (C) Representative images of Alizarin Red S staining at day 21 of the bone nodule assay. (D) Cumulative data of C. Where applicable, data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, ANOVA, n = (3-5).

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