Fetuin-A is an immunomodulator and a potential therapeutic option in BMP4-dependent heterotopic ossification and associated bone mass loss  

作　　者：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 

机构地区：[1]Department of Pathophysiology,School of Basic Medical Sciences,Anhui Medical University,Hefei,China [2]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,Hefei,China [3]Institute of Immunology,University of Science and Technology of China,Hefei,China [4]Department of Orthopaedics,The First Affiliated Hospital of USTC,Hefei,China [5]Department of Orthopaedics,Fuyang Hospital of Anhui Medical University,Fuyang,China

出　　处：《Bone Research》2022年第4期867-881,共15页骨研究（英文版）

基　　金：supported by the National Key Research and Development Program of China(reference number 2019YFA0801800);the Natural Science Foundation of China(reference numbers 32070916,82102573,8157152,81472087,81670097 and 81870085);the Natural Science Foundation of Anhui Province(reference numbers 1508085MC45 and 1908085QH359).

摘　　要：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.

关 键 词：PD1 THERAPEUTIC inhibited 

分 类 号：R681[医药卫生—骨科学]