Inflammatory cytokines induce a unique mineralizing phenotype in mesenchymal stem cells derived from human bone marrow

Elisabeth Ferreira, Ryan M. Porter, Nathalie Wehling, Regina P. O'Sullivan, Fangjun Liu, Adele Boskey, Daniel M. Estok, Mitchell B. Harris, Mark S. Vrahas, Christopher H Evans, James W. Wells

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Bone marrow contains mesenchymal stem cells (MSCs) that can differentiate along multiple mesenchymal lineages. In this capacity they are thought to be important in the intrinsic turnover and repair of connective tissues while also serving as a basis for tissue engineering and regenerative medicine. However, little is known of the biological responses of human MSCs to inflammatory conditions. When cultured with IL-1β, marrow- derived MSCs from 8 of 10 human subjects deposited copious hydroxyapatite, in which authenticity was confirmed by Fourier transform infrared spectroscopy. Transmission electron microscopy revealed the production of fine needles of hydroxyapatite in conjunction with matrix vesicles. Alkaline phosphatase activity did not increase in response to inflammatory mediators, but PPi production fell, reflecting lower ectonucleotide pyrophosphatase activity in cells and matrix vesicles. Because PPi is the major physiological inhibitor of mineralization, its decline generated permissive conditions for hydroxyapatite formation. This is in contrast to MSCs treated with dexamethasone, where PPi levels did not fall and mineralization was fuelled by a large and rapid increase in alkaline phosphatase activity. Bone sialoprotein was the only osteoblast marker strongly induced by IL-1β; thus these cells do not become osteoblasts despite depositing abundant mineral. RT-PCR did not detect transcripts indicative of alternative mesenchymal lineages, including chondrocytes, myoblasts, adipocytes, ligament, tendon, or vascular smooth muscle cells. IL-1β phosphorylated multiple MAPKs and activated nuclear factor-κB (NF-κB). Certain inhibitors of MAPK and PI3K, but not NF-κB, prevented mineralization. The findings are of importance to soft tissue mineralization, tissue engineering, and regenerative medicine.

Original languageEnglish (US)
Pages (from-to)29494-29505
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number41
DOIs
StatePublished - Oct 11 2013
Externally publishedYes

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Stem cells
Mesenchymal Stromal Cells
Bone
Durapatite
Bone Marrow
Interleukin-1
Cytokines
Phenotype
Regenerative Medicine
Osteoblasts
Tissue Engineering
Tissue engineering
Alkaline Phosphatase
Integrin-Binding Sialoprotein
Tissue
Pyrophosphatases
Myoblasts
Ligaments
Tendons
Fourier Transform Infrared Spectroscopy

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Ferreira, E., Porter, R. M., Wehling, N., O'Sullivan, R. P., Liu, F., Boskey, A., ... Wells, J. W. (2013). Inflammatory cytokines induce a unique mineralizing phenotype in mesenchymal stem cells derived from human bone marrow. Journal of Biological Chemistry, 288(41), 29494-29505. https://doi.org/10.1074/jbc.M113.471268

Inflammatory cytokines induce a unique mineralizing phenotype in mesenchymal stem cells derived from human bone marrow. / Ferreira, Elisabeth; Porter, Ryan M.; Wehling, Nathalie; O'Sullivan, Regina P.; Liu, Fangjun; Boskey, Adele; Estok, Daniel M.; Harris, Mitchell B.; Vrahas, Mark S.; Evans, Christopher H; Wells, James W.

In: Journal of Biological Chemistry, Vol. 288, No. 41, 11.10.2013, p. 29494-29505.

Research output: Contribution to journalArticle

Ferreira, E, Porter, RM, Wehling, N, O'Sullivan, RP, Liu, F, Boskey, A, Estok, DM, Harris, MB, Vrahas, MS, Evans, CH & Wells, JW 2013, 'Inflammatory cytokines induce a unique mineralizing phenotype in mesenchymal stem cells derived from human bone marrow', Journal of Biological Chemistry, vol. 288, no. 41, pp. 29494-29505. https://doi.org/10.1074/jbc.M113.471268
Ferreira, Elisabeth ; Porter, Ryan M. ; Wehling, Nathalie ; O'Sullivan, Regina P. ; Liu, Fangjun ; Boskey, Adele ; Estok, Daniel M. ; Harris, Mitchell B. ; Vrahas, Mark S. ; Evans, Christopher H ; Wells, James W. / Inflammatory cytokines induce a unique mineralizing phenotype in mesenchymal stem cells derived from human bone marrow. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 41. pp. 29494-29505.
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