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

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.

Arsenic exposure increases susceptibility to Ptpn11-induced malignancy in mouse embryonic fibroblasts through mitochondrial hypermetabolism.

OBJECTIVE: To explore the synergistic effect and metabolic mechanism of chronic arsenic exposure and PTPN11 gain-of-function mutation on tumorigenesis. METHODS: Arsenic-transformed Ptpn11+/+ (WT-As) and Ptpn11D61G/+ -mutant (D61G-As) mouse embryonic fibroblasts (MEFs) were established by chronic treatment of low-dose arsenic. We used cell counting, plate colony and soft agar colony formation, and a nude mouse xenograft model to detect malignant transformation and tumorigenesis in vitro and in vivo. To detect mitochondrial oxidative phosphorylation (OXPHOS), we used Seahorse real-time cell metabolic analysis as well as adenosine triphosphate (ATP) and ROS production assays. Lastly, we examined mTOR signaling pathway changes by western blotting. RESULTS: Low-dose arsenic exposure promoted WT MEFs proliferation and exacerbated malignancy driven by Ptpn11D61G/+ mutation. Additionally, Ptpn11D61G/+ -mutant MEFs exhibited increased mitochondrial metabolism and low-dose arsenic amplified this malignant metabolic activity. Mechanistically, the mTOR signaling pathway was activated in Ptpn11D61G/+ -mutant MEFs and was further phosphorylated in arsenic-treated MEFs expressing Ptpn11D61G/+ . Critically, tumorigenesis induced by the synergistic effect of low-dose arsenic and Ptpn11D61G/+ mutation was prevented by mTOR pathway inhibition via rapamycin. CONCLUSION: This study found that metabolic reprogramming, particularly mitochondrial hyperactivation, is a core mechanism underlying tumorigenesis induced by the synergistic effect of Ptpn11D61G/+ mutation and arsenic exposure. Furthermore, these findings suggested mTOR is a therapeutic target for Ptpn11-associated cancers.