Macrophages Driving Heterotopic Ossification: Convergence of Genetically-Driven and Trauma-Driven Mechanisms

Abstract

We read with great interest the recent article in the Journal of Bone and Mineral Research by Convente and colleagues, "Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1 R206H mouse model of fibrodysplasia ossificans progressiva." (1) This article reports that muscle injury caused by intramuscular injection of cardiotoxin from Naja mossambica mossambica venom into the Acvr1 R206H mouse causes the development of heterotopic ossifications (HO) at the injury site. They demonstrated exacerbated macrophage and mast cell accumulation in Acvr1 R206H mice and showed that depletion of macrophages in vivo with clodronate-loaded liposomes, genetic impairment of mast cells, or a combination of both approaches substantially reduced the volume of HO. The authors conclude that the immune system, particularly macrophages and mast cells, are major contributors to the initiation and development of HO in fibrodysplasia ossificans progressiva (FOP).This finding of macrophage involvement in the development of HO in FOP is wholly consistent with our previously published work using identical methodology to show that macrophages mediate the development of HO in wild-type mice with spinal cord injury (SCI). (2) In that work, we showed that the combination of SCI with intramuscular injection of cardiotoxin from Naja mossambica mossambica venom causes development of neurogenic HO in wild-type mice. The development of HO in SCI mice recapitulated the clinical features of neurogenic HO in patients with SCI or traumatic brain injury. We also showed that concomitant depletion of macrophages in vivo, using clodronate-loaded liposomes, dramatically reduced the volume of HO in this model of neurogenic HO after SCI. (2) Convente and colleagues suggest that Substance P, as a neuroinflammatory modulator, may be a major molecular driver of HO. We reported significantly elevated Substance P in serum of patients with neurogenic HO, but that Substance P antagonism was modestly protective in the neurogenic HO mouse model. (2) We concluded that macrophages are key drivers of neurogenic HO in this model.The role of macrophages in promoting bone formation in HO, both in our model of trauma-induced HO and in Convente and colleagues' Acvr1 mutant model of HO in FOP, (1) is consistent with our previously published work showing a key role of macrophages in the maintenance of functional osteoblasts, bone formation, and bone repair. (3)(4)(5)(6) We have now identified that the range of cytokines induced in macrophages by cardiotoxin injection includes oncostatin M, and secretion of oncostatin M by inflammatory monocytes and macrophages infiltrating the injured muscle is a key driver of HO development and formation of heterotopic hematopoietic stem cell niches in humans and mice with SCI. (7) In conclusion, we wish to highlight a point that seems to have been overlooked by Convente and colleagues, which is that even though HO development in these two clinically distinct situations (genetically-driven FOP versus trauma-driven neur...

The Survey of Cells Responsible for Heterotopic Ossification Development in Skeletal Muscles—Human and Mouse Models

“…Recent studies showed the role of immune response cells, especially monocytes/macrophages, at the early stages of trauma-induced HO development [ 6 ]. They confirm the importance of macrophages in the induction of neurogenic and genetic forms of HO [ 7 ]. Activated macrophages express osteoinductive signaling factors in the course of HO pathogenesis.…”

Inhibition of JAK1/2 Tyrosine Kinases Reduces Neurogenic Heterotopic Ossification After Spinal Cord Injury

“…In this model the combination of two injuries is necessary to trigger NHO development in the muscle: a severe lesion of the central nervous system such as a SCI in combination with a muscle injury (13). Development of NHO following spinal cord transection in this model was triggered by macrophages infiltrating damaged muscles exclusively in the context of a complete SCI (13, 14). More recently we established that the inflammatory cytokine oncostatin M (OSM) secreted in part by macrophages infiltrating the inflamed muscle contribute to both human and mouse NHO development (15).…”

Interleukin-1 is overexpressed in injured muscles following spinal cord injury and promotes neurogenic heterotopic ossification

“…The enhancing effect of CSF1R tyrosine kinase inhibitor GW2580 on NHO development was also surprising because CSF1R signaling is necessary to maintain many tissue-resident macrophages and osteoclasts but dispensable to monocyte production in the bone marrow (39,40) although extra-physiological treatment with stable CSF-1 protein considerably enhances monopoiesis (29,40) . As macrophages are necessary to the development of SCI-induced NHO (8) as well as genetically-driven HO development in fibrodysplasia ossificans progressiva (17,41) , we anticipated that inhibition of CSF1R signaling would reduce NHO formation. The opposite effect that we observed on NHO formation in vivo may be due to the complex function of CSF-1 on macrophage biology.…”