Suppression of Overactive Insulin-Like Growth Factor 1 Attenuates Trauma-Induced Heterotopic Ossification in Mice

Abstract

Heterotopic ossification (HO) is the ectopic bone formation in soft tissues. Aside from hereditary HO, traumatic HO is common after orthopedic surgery, combat-related injuries, severe burns, or neurologic injuries. Recently, mTOR has been demonstrated to be involved in the chondrogenic and osteogenic processes of HO formation. However, its upstream signaling mechanism remains unknown. In this study, using an Achilles tendon puncture-induced HO model, we revealed that overactive insulin-like growth factor 1 (IGF-1) was involved in the progression of HO in mice. Micro-CT imaging showed that IGF-1 not only accelerated the rate of osteogenesis and increased ectopic bone volume but also induced spontaneous ectopic bone formation in undamaged Achilles tendons. Blocking IGF-1 activity with IGF-1 antibody or IGF-1 receptor (IGF-1R) inhibitor Picropodophyllin significantly inhibited HO formation. Mechanistically, IGF-1/IGF-1R activates PI3K/Akt signaling to promote the phosphorylation of mTOR, resulting in the chondrogenic and osteogenic differentiation of tendon-derived stem cells (TDSCs) into chondrocytes and osteoblasts in vitro and in vivo. Inhibitors of PI3K (LY294002) and mTOR (Rapamycin) both suppressed the IGF-1-stimulated mTOR signal and mitigated the formation of ectopic bones significantly. In conclusion, our results indicated that IGF-1 mediated the progression of traumatic HO through PI3K/Akt/mTOR signaling, and suppressing IGF-1 signaling cascades attenuated HO formation, providing a promising therapeutic strategy targeting HO.