Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

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.

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.

3D printed porous titanium filled with mineralized UV-responsive chitosan hydrogel promotes cell proliferation and osteogenesis in vitro

The modification of 3D printed porous titanium(Ti),especially for the internal pore structure,is critical and has received more attention to promoting its osteogenesis for clinical use.Ultra-violet(UV)responsive chitosan(CSMA),as an injectable filling material,was firstly incorporated into porous Ti,and then CSMA was in-situ mineralized by carbon oxide(CO_(2))diffusion(CSMA/CaCO_(3)).Their physical-chemical and biological properties were investigated in vitro.CaCO_(3) crystals within CSMA hydrogels were successfully deposited into pores of porous Ti,which exhibited favorable biocompatibility.Ti implants filled with CSMA/CaCO_(3) promoted adhesion and proliferation of bone mesenchymal stem cells(BMSCs).Moreover,Ti implant filled CSMA/CaCO_(3) hydrogels could increase alkaline phosphatase(ALP)activities,up-regulate osteopontin(OPN)and osteocalcin(OCN)expression levels,and enhance extracellular mineralization.3D printed porous Ti filled with mineralized UV-responsive chitosan hydrogel could promote proliferation and osteogenesis of BMSCs,and have great potential for the modification of porous Ti implants in bone tissue engineering.