Inhibition of the Oxygen Sensor PHD2 Enhances Tissue-Engineered Endochondral Bone Formation.
(2019) Journal of Bone and Mineral Research — Vol. 34, n° 2, p. 333-348 (2019)
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- Abstract
- Tissue engineering holds great promise for bone regenerative medicine, but clinical translation remains challenging. An important factor is the low cell survival after implantation, primarily caused by the lack of functional vasculature at the bone defect. Interestingly, bone development and repair initiate predominantly via an avascular cartilage template, indicating that chondrocytes are adapted to limited vascularization. Given these advantageous properties of chondrocytes, we questioned whether tissue-engineered cartilage intermediates implanted ectopically in mice are able to form bone, even when the volume size increases. Here, we show that endochondral ossification proceeds efficiently when implant size is limited (≤30 mm ), but chondrogenesis and matrix synthesis are impaired in the center of larger implants, leading to a fibrotic core. Increasing the level of angiogenic growth factors does not improve this outcome, because this strategy enhances peripheral bone formation, but disrupts the conversion of cartilage into bone in the center, resulting in a fibrotic core, even in small implants. On the other hand, activation of hypoxia signaling in cells before implantation stimulates chondrogenesis and matrix production, which culminates in enhanced bone formation throughout the entire implant. Together, our results show that induction of angiogenesis alone may lead to adverse effects during endochondral bone repair, whereas activation of hypoxia signaling represents a superior therapeutic strategy to improve endochondral bone regeneration in large tissue-engineered implants. © 2018 American Society for Bone and Mineral Research.
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Citations
Stiers, P.-J., Stegen, S., van Gastel, N., Van Looveren, R., Torrekens, S., & Carmeliet, G. (2019). Inhibition of the Oxygen Sensor PHD2 Enhances Tissue-Engineered Endochondral Bone Formation. Journal of Bone and Mineral Research, 34(2), 333-348. https://doi.org/10.1002/jbmr.3599 (Original work published 2019)