MFG-E8 promotes tendon-bone healing by regualting macrophage efferocytosis and M2 polarization after anterior cruciate ligament reconstruction

Journal of Orthopaedic TranslationVolume 34, May 2022, Pages 11-21Journal of Orthopaedic TranslationAbstractBackground

Scar tissue formation at the tendon-bone interface caused by excessive inflammation leads to insufficient healing strength, while the phagocytic clearance of dying cells (efferocytosis) has profound consequences on macrophage polarisation and the inflammatory response. Modulating the inflammatory microenvironment may have satisfactory curative effects in patients with anterior cruciate ligament reconstruction (ACLR).

Methods

Bone marrow-derived macrophages (BMDMs) and polymorphonuclear leukocytes (PMNs) were harvested from bone marrow. The effects of milk fat globulin protein E8 (MFG-E8) on macrophage polarisation were compared with those of M1 and M2 macrophages induced by conventional methods. The BMDMs and apoptotic PMNs co-culture system was used to assess the efficiency of efferocytosis. The biological functions of MFG-E8 in tendon-bone healing by regulating macrophage efferocytosis and polarisation were further investigated using a rat ACLR model.

Results

BMDMs and PMNs were successfully isolated. Compared to conventional induction methods, MFG-E8 alone did not significantly induce macrophage M1 or M2 polarisation, but it could partially reverse the expression of inducible nitric oxide synthase (iNOS) in M1 macrophages. In vitro studies revealed that appropriate dosing of MFG-E8 could significantly promote the efficiency of macrophage efferocytosis and subsequently increase M2 polarisation. More importantly, significantly increased peri-tunnel new bone formation, tighter connected interface and better mechanical properties were observed after ACLR when treated with MFG-E8 in vivo. We further demonstrated that MFG-E8 remarkably facilitated the clearance of apoptotic cells and increased the number of M2 macrophages at the interface between the tendon graft and bone tunnel in the early postoperative stage.

Conclusion

MFG-E8 promoted tendon-bone healing histologically and biomechanically, probably by the regulation of inflammatory processes via macrophage efferocytosis and M2 polarisation.

The translational potential of this article: Regulation of macrophage efferocytosis and M2 polarization by MFG-E8 is expected to be a therapeutic strategy for promoting tendon-bone healing in patients undergoing ACLR.

Keywords

Anterior cruciate ligament reconstruction

Tendon-bone healing

Milk fat globulin protein E8

Efferocytosis

Macrophage polarization

© 2022 The Authors. Published by Elsevier (Singapore) Pte Ltd on behalf of Chinese Speaking Orthopaedic Society.

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