A bone fracture can be defined as a partial or complete break in the continuity of a bone associated with soft tissue injury. Fractures can be closed (no protrusion on the outside) or open (obvious soft tissue damage).
Bone Fracture
Over the last 100 years, reports have recorded high mortality and a high rate of amputations with open fractures. This was in part due to the fact that doctors wanted to avoid death at all costs. Now, the focus has shifted from the preservation of life and what is left of the limb to the preservation of function and prevention of complications.
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To adequately ensure fracture healing, there must be good soft tissue coverage and vascularization. Compromised blood supply with little or no growth of new blood vessels is a current issue of clinical concern. Osteoblasts (bone-forming cells) need sufficient oxygen and nutrients from blood vessels to institute proper healing.
Scientists claim that applying mechanical load on fractured bones induces blood vessel formation, fracture repair, and bone regeneration through the activation of some specific genes. However, the outcome depends on the magnitude of the load applied.
The genes that have been identified are; transcriptional co-activator with PDZ-binding motif (TAZ), Yes-associated protein (YAP), and Cysteine-rich angiogenic inducer 61 (Cyr61.)
Cyr61 induces blood vessel formation
Lang et al. discovered that Cyr61, a potent growth factor, regulates the actions of TAZ and YAP to stimulate blood vessel formation and fracture healing both in vivo and in vitro. In the study, they carried out cellular mapping to determine the actions of Cyr61 in mice and discovered a strong association between Cyr61 and YAP. They were also able to establish a firm link between Cyr61 and blood vessels.
For the in vitro experiment, human mesenchymal stromal cells were used. They evaluated the action of the exogenous form of Cyr61 during different mechanical states. Cyr61 therapy caused the formation of endothelial cells and the canalization and maturation of new blood vessels.
However, two things were noted. Cyr61 did not promote new bone formation either in the fracture site or in vitro and the blood-vessel effect was cut short by early application of mechanical load. This inadvertently means that the effect of Cyr61 is time-frame specific.
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YAP and TAZ genes were also identified as key factors that regulate bone healing. It was discovered that the elimination of these genes caused diminished vascularization and insufficient osteoblast formation. These findings were concomitant with reduced Cyr61 expression and show that Cyr61 regulates the YAP/TAZ pathway.
Clinical Significance
Cyr61 therapy is going to be very useful for fracture patients. Targeting the YAP/TAZ/Cyr61 pathway can induce the formation of new blood vessels, encourage good fracture healing, promote bone strength, and offer better clinical outcomes. The growth-factor attributes of Cyr61 can also be applied to other clinical conditions where the formation of new blood vessels and tissue repair are needed.
It has been discovered that Cyr61 plays a huge role in the development of some cancers and the regulation of various inflammatory conditions. High levels of the protein have been recorded in breast, ovarian, and prostate carcinomas. A therapy that targets the Cyr61 pathway will be appreciated by both physicians and patients.
References
Lang, A., Eastburn, E. A., Younesi, M., Nijsure, M. P., Siciliano, C., Pranatharthi-Haran, A., Panebianco, C. J., Seidl, E., Tang, R., Alsberg, E., Willett, N. J., Gottardi, R., Huh, D., & Boerckel, J. D. (2024, April 6). Cyr61 delivery promotes angiogenesis during bone fracture repair. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2024.04.05.588239
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