Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications

JCI Insight. 2017 Nov 2;2(21):e96034. doi: 10.1172/jci.insight.96034.

Abstract

Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles surrounding joints following spinal cord or brain injury. We investigated the mechanisms of NHO formation in 64 patients and a mouse model of spinal cord injury-induced NHO. We show that marrow from human NHOs contains hematopoietic stem cell (HSC) niches, in which mesenchymal stromal cells (MSCs) and endothelial cells provide an environment supporting HSC maintenance, proliferation, and differentiation. The transcriptomic signature of MSCs from NHOs shows a neuronal imprinting associated with a molecular network required for HSC support. We demonstrate that oncostatin M (OSM) produced by activated macrophages promotes osteoblastic differentiation and mineralization of human muscle-derived stromal cells surrounding NHOs. The key role of OSM was confirmed using an experimental model of NHO in mice defective for the OSM receptor (OSMR). Our results provide strong evidence that macrophages contribute to NHO formation through the osteogenic action of OSM on muscle cells within an inflammatory context and suggest that OSM/OSMR could be a suitable therapeutic target. Altogether, the evidence of HSCs in ectopic bones growing at the expense of soft tissue in spinal cord/brain-injured patients indicates that inflammation and muscle contribute to HSC regulation by the brain-bone-blood triad.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, CD34
  • Brain Injuries
  • Cell Differentiation
  • Cell Proliferation
  • Endothelial Cells
  • Female
  • Hematopoiesis
  • Hematopoietic Stem Cells
  • Heterografts
  • Humans
  • Macrophages / metabolism*
  • Mesenchymal Stem Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oncostatin M / metabolism*
  • Oncostatin M Receptor beta Subunit
  • Ossification, Heterotopic / immunology*
  • Ossification, Heterotopic / metabolism*
  • Ossification, Heterotopic / pathology
  • Osteogenesis
  • Spinal Cord
  • Transcriptome

Substances

  • Antigens, CD34
  • OSMR protein, human
  • Oncostatin M Receptor beta Subunit
  • Oncostatin M

Grant support

This research was funded by Project Grant 1101620 from the DGA (French Government Defense Procurement and Technology Agency) to authors FT, FG, JJL and MCLBK