Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

Chen Kan, Jiazhao Yang, Ding Na, Yuanhong Xu, Baixia Yang, Haodong Zhao, Huadong Lu, Yuyun Li, Keqin Zhang, Tammy L. McGuire, John A. Kessler*, Lixin Kan

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Heterotopic ossification (HO), true bone formation in soft tissue, is closely associated with abnormal injury/immune responses. We hypothesized that a key underlying mechanism of HO might be injury-induced dysregulation of immune checkpoint proteins (ICs). We found that the earliest stages of HO are characterized by enhanced infiltration of polarized macrophages into sites of minor injuries in an animal model of HO. The non-specific immune suppressants, Rapamycin and Ebselen, prevented HO providing evidence of the central role of the immune responses. We examined the expression pattern of ICs and found that they are dysregulated in HO lesions. More importantly, loss of function of inhibitory ICs (including PD1, PD-L1, and CD152) markedly inhibited HO, whereas loss of function of stimulatory ICs (including CD40L and OX-40L) facilitated HO. These findings suggest that IC inhibitors may provide a therapeutic approach to prevent or limit the extent of HO.

Original languageEnglish (US)
Article number33
JournalBone Research
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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    Kan, C., Yang, J., Na, D., Xu, Y., Yang, B., Zhao, H., Lu, H., Li, Y., Zhang, K., McGuire, T. L., Kessler, J. A., & Kan, L. (2019). Inhibition of immune checkpoints prevents injury-induced heterotopic ossification. Bone Research, 7(1), [33]. https://doi.org/10.1038/s41413-019-0074-7