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How Mesenchymal Progenitors Promote Bone Healing

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Review of  “Hypoxia and Reactive Oxygen Species Homeostasis in Mesenchymal Progenitor Cells Define a Molecular Mechanism for Fracture Nonunion” from Stem Cells by Stuart P. Atkinson

While bone tissue maintains its regenerative abilities in the human adult, the process of fracture healing can sometimes fail [1]. However, the cellular and molecular mechanisms which mediate this failure remain incompletely understood [2].

In order to fill this knowledge gap, the laboratory of Froilán Granero-Moltó (Clínica Universidad de Navarra, Pamplona, Spain) have been working on a specific hypothesis; that after fracture, the microenvironment surrounding the fracture, characterized by hypoxia and hematoma formation, fails to trigger Bmp2 expression [3] in mesenchymal progenitors, cells known to be the mediators of bone regeneration [4].

Their new Stem Cells study now discusses the importance of hypoxic signaling and Bmp2 expression to fracture healing by mesenchymal progenitors in the hope of finding new therapeutic targets [5].

To explore the mechanisms controlling bone healing, the study employed a model of closed non-stabilized fracture of the tibia in transgenic mice carrying a Bmp2 reporter. This allowed the researchers to show that a hypoxic tissue environment and hematoma presence correlated to an increase in Bmp2 during the early stages of natural healing of bone fractures. Furthermore, the authors also demonstrated that interruption in hypoxic signaling (via PX-12, a thioredoxin inhibitor) significantly impaired the initiation of fracture healing and inhibited Bmp2 expression.

To next explore this mechanism in humans, the study examined the response of mesenchymal progenitor-containing bone explants to hypoxia in vitro. While the authors observed increased BMP2 expression throughout the bone sections in response to lower oxygen levels, mesenchymal progenitors seemed to express higher levels as compared to the surrounding tissues. Analysis of isolated bone mesenchymal progenitors then confirmed that hypoxic signaling induced BMP2 expression, but only in the presence of hematoma-derived growth factors.

These findings will hopefully take us some way forward in understanding the key mechanisms at play during bone healing (See Figure) and provide us with bona fide cellular (mesenchymal progenitors) and molecular (BMP2/hypoxic regulators) therapeutic targets in cases where normal healing does not occur. Therapies based on these targets will not only potentially do away with invasive surgical treatments, but may also provide a better quality of life for the elderly and infirm and those who suffer from various bone-related maladies.

References

  1. Marsh D. Concepts of fracture union, delayed union, and nonunion. Clin Orthop Relat Res 1998;S22-30.
  2. Choi P, Ogilvie C, Thompson Z, et al. Cellular and molecular characterization of a murine non-union model. J Orthop Res 2004;22:1100-1107.
  3. Cho TJ, Gerstenfeld LC, and Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 2002;17:513-520.
  4. Dawson JI, Kanczler J, Tare R, et al. Concise review: bridging the gap: bone regeneration using skeletal stem cell-based strategies - where are we now? Stem Cells 2014;32:35-44.
  5. Muinos-Lopez E, Ripalda-Cemborain P, Lopez-Martinez T, et al. Hypoxia and Reactive Oxygen Species Homeostasis in Mesenchymal Progenitor Cells Define a Molecular Mechanism for Fracture Nonunion. Stem Cells 2016;34:2342-2353.