Format

Send to

Choose Destination
J Orthop Res. 2017 Nov;35(11):2378-2385. doi: 10.1002/jor.23553. Epub 2017 Mar 13.

Pro-inflammatory M1 macrophages promote Osteogenesis by mesenchymal stem cells via the COX-2-prostaglandin E2 pathway.

Author information

1
Department of Orthopaedic Surgery, Stanford University, Stanford, California.
2
Laboratoire de Biomécanique et Biomatériaux Ostéo-Articulaires - UMR CNRS 7052, Faculté de Médecine - Université Paris7, Paris, France.
3
Department of Oral and Maxillofacial Surgery, University of Chile, Santiago, Chile.
4
Department of Medicine, Clinicum, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.
5
Department of Bioengineering, Stanford University, Stanford, California.

Abstract

Bone fractures are among the most common orthopaedic problems that affect individuals of all ages. Immediately after injury, activated macrophages dynamically contribute to and regulate an acute inflammatory response that involves other cells at the injury site, including mesenchymal stem cells (MSCs). These macrophages and MSCs work in concert to modulate bone healing. In this study, we co-cultured undifferentiated M0, pro-inflammatory M1, and anti-inflammatory M2 macrophages with primary murine MSCs in vitro to determine the cross-talk between polarized macrophages and MSCs and their effects on osteogenesis. After 4 weeks of co-culture, MSCs grown with macrophages, especially M1 macrophages, had enhanced bone mineralization compared to MSCs grown alone. The level of bone formation after 4 weeks of culture was closely associated with prostaglandin E2 (PGE2) secretion early in osteogenesis. Treatment with celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, significantly reduced bone mineralization in all co-cultures but most dramatically in the M1-MSC co-culture. We also found that the presence of macrophages reduced the secretion of osteoprotegerin (OPG), the decoy RANKL receptor, suggesting that macrophages may indirectly modulate osteoclast activity in addition to enhancing bone formation. Taken together, these findings suggest that an initial pro-inflammatory phase modulated by M1 macrophages promotes osteogenesis in MSCs via the COX-2-PGE2 pathway. Understanding the complex interactions between macrophages and MSCs provide opportunities to optimize bone healing and other regenerative processes via modulation of the inflammatory response. This study provides one possible biological mechanism for the adverse effects of non-steroidal anti-inflammatory drugs on fracture healing and bone regeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2378-2385, 2017.

KEYWORDS:

fracture healing; mesenchymal stem cells; osteogenesis; polarized macrophages

PMID:
28248001
PMCID:
PMC5581298
DOI:
10.1002/jor.23553
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center