TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells

Glass, Graeme E, Chan, James K, Freidin, Andrew, Feldmann, Marc, Horwood, Nicole J ORCID: https://orcid.org/0000-0002-6344-1677 and Nanchahal, Jagdeep (2011) TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 108 (4). pp. 1585-1590. ISSN 1091-6490

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Abstract

With an aging population, skeletal fractures are increasing in incidence, including the typical closed and the less common open fractures in normal bone, as well as fragility fractures in patients with osteoporosis. For the older age group, there is an urgent unmet need to induce predictable bone formation as well as improve implant fixation in situations such as hip joint replacement. Using a murine model of slow-healing fractures, we have previously shown that coverage of the fracture with muscle accelerated fracture healing and increased union strength. Here, we show that cells from muscle harvested after 3 d of exposure to an adjacent fracture differentiate into osteoblasts and form bone nodules in vitro. The osteogenic potential of these cells exceeds that of adipose and skin-derived stromal cells and is equivalent to bone marrow stromal cells. Supernatants from human fractured tibial bone fragments promote osteogenesis and migration of muscle-derived stromal cells (MDSC) in vitro. The main factor responsible for this is TNF-α, which promotes first MDSC migration, then osteogenic differentiation at low concentrations. However, TNF-α is inhibitory at high concentrations. In our murine model, addition of TNF-α at 1 ng/mL at the fracture site accelerated healing. These data indicate that manipulating the local inflammatory environment to recruit, then differentiate adjacent MDSC, may be a simple yet effective way to enhance bone formation and accelerate fracture repair. Our findings are based on a combination of human specimens and an in vivo murine model and may, therefore, translate to clinical care.

Item Type:	Article
Uncontrolled Keywords:	metabolism,metabolism,animals,drug effects,drug effects,drug effects,cells, cultured,pharmacology,pharmacology,dose-response relationship, drug,flow cytometry,drug effects,physiopathology,humans,mice,mice, inbred c57bl,cytology,cytology,drug effects,pharmacology,cytology,metabolism,pharmacology
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	06 Mar 2019 10:30
Last Modified:	25 Sep 2024 13:57
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70138
DOI:	10.1073/pnas.1018501108

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