Fetuin-A is an immunomodulator and a potential therapeutic option in BMP4-dependent heterotopic ossification and associated bone mass loss
Chen Kan,
Jiazhao Yang,
Haitao Fan,
Yuanjuan Dai,
Xingxing Wang,
Rui Chen,
Jia Liu,
Xiangyue Meng,
Wei Wang,
Guiling Li,
Jiao Zhou,
Ya Zhang,
Wanbo Zhu,
Shiyuan Fang,
Haiming Wei,
Hong Zheng,
Siying Wang,
Fang Ni
Affiliations
Chen Kan
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Jiazhao Yang
Department of Orthopaedics, The First Affiliated Hospital of USTC
Haitao Fan
Department of Orthopaedics, Fuyang Hospital of Anhui Medical University
Yuanjuan Dai
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Xingxing Wang
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Rui Chen
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Jia Liu
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Xiangyue Meng
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Wei Wang
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Guiling Li
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Jiao Zhou
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Ya Zhang
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Wanbo Zhu
Department of Orthopaedics, The First Affiliated Hospital of USTC
Shiyuan Fang
Department of Orthopaedics, The First Affiliated Hospital of USTC
Haiming Wei
Department of Hematology, The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China
Hong Zheng
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Siying Wang
Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University
Fang Ni
Department of Hematology, The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China
Abstract Heterotopic ossification (HO) is the abnormal formation of bone in extraskeletal sites. However, the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear. Here, we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO. Moreover, we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury (dpi). In contrast, a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi. Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss. We further demonstrated that fetuin-A (FetA), which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone, acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization, leading to immunosuppression. Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss. Collectively, our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.