The clinically observable signs of tissue ageing that occur in elderly individuals-such as increased stiffness of the joints and increased fragility of the bones-arise from nanoscale changes in the two major structural proteins of the body, collagen and elastin. The same protein changes are thought to explain increased bone fragility in diabetes, a disease long described as having hallmarks of “accelerated aging.” In prior studies by the research team, the Donnelly Lab has developed methods to image spatial distributions of fluorescent crosslinks in the collagen that increase with tissue age and embrittle bone. Recent epidemiologic studies have indicated that other, non-fluorescent crosslinks may be more strongly associated with increased risk of clinical fractures [2].

In this project, we focus on the development of new markers of collagen aging and degradation by leveraging fluorescent silica core-poly (ethylene glycol) (PEG) shell hybrid nanoparticles (C’-dots) developed in the Wiesner Lab and validated in bone [3]. These markers can potentially be used as diagnostics of bone fragility.

Future work will extend the targeting capabilities of C’-dots from the cartilage extracellular matrix to key molecular species within the bone matrix, specifically advanced glycation endproducts (AGEs), which are well-known contributors to diabetic and age-related bone deterioration.

Collaborator: Prof. Uli Wiesner

Figure. Confocal microscopy images of Calcein AM and C’-dots in human tibia plateau slices

References:

  1. Lekkala, S., Sacher, S. E., Taylor, E. A., Williams, R. M., Moseley, K. F., & Donnelly, E. (2022). Increased advanced glycation end products, stiffness, and hardness in iliac crest bone from postmenopausal women with type 2 diabetes mellitus on insulin. Journal of Bone and Mineral Research, 38(2), 261–277. https://doi.org/10.1002/jbmr.4757
  2. Dhaliwal, R., Ewing, S. K., Vashishth, D., Semba, R. D., & Schwartz, A. V. (2022). Greater carboxy-methyl-lysine is associated with increased fracture risk in type 2 diabetes. Journal of Bone and Mineral Research, 37(2), 265–272. https://doi.org/10.1002/jbmr.4466
  3. Chiou, A. E., Hinckley, J. A., Khaitan, R., Varsano, N., Wang, J., Malarkey, H. F. V., Hernandez, C. J., Williams, R. M., Estroff, L. A., Weiner, S., Addadi, L., Wiesner, U. B., & Fischbach, C. (2020). Fluorescent silica nanoparticles to label metastatic tumor cells in mineralized bone microenvironments. Small, 17(3), 2001432. https://doi.org/10.1002/smll.202001432