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

doi:10.1038/s41413-019-0074-7

Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

Bone Res. 2019 Nov 1:7:33. doi: 10.1038/s41413-019-0074-7. eCollection 2019.

Authors

Chen Kan^#¹, Jiazhao Yang^#², Ding Na¹, Yuanhong Xu³, Baixia Yang³, Haodong Zhao⁴, Huadong Lu⁵, Yuyun Li⁶, Keqin Zhang⁷, Tammy L McGuire⁸, John A Kessler⁸, Lixin Kan^{1

8}

Affiliations

¹ 1School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, 230032 Hefei, Anhui China.
² 2Department of Traumatic Orthopedics, Anhui Provincial Hospital, The First Affiliated Hospital of China University of Science and Technology, 233000 Hefei, Anhui China.
³ 3Department of Clinical Laboratory, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui China.
⁴ 4Department of Emergency, the First Affiliated Hospital, Anhui Medical University, 230000 Hefei, Anhui China.
⁵ 5Emergency Medicine Center, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui China.
⁶ 6Department of Medical Laboratory Science, Bengbu Medical College, 2600 Donghai Avenue, Longzihu, 233030 Bengbu, Anhui China.
⁷ 7Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
⁸ 8Department of Neurology, Northwestern University, Ward Building 10-233, 303 East Chicago Avenue, Chicago, IL 60611-3008 USA.

^# Contributed equally.

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.

Keywords: Bone; Physiology.

Grants and funding

R01 AR066539/AR/NIAMS NIH HHS/United States