Kaitlyn Broz, Institute of Materials Science & Engineering  Doctoral Candidate

Type 2 Diabetes (T2D) is an increasingly prevalent disease which can be detrimental to a person’s quality of life, especially when combined with comorbidities. Some of the most significant comorbidities occur in the musculoskeletal system where skeletal fragility, osteoarthritis, and low back pain are prevalent. Vertebral fractures specifically are 3.1xs more likely to occur in post-menopausal women with T2D, a fact that is counterintuitive to T2D patients presenting with an increase in bone mineral density (BMD). This disparity between vertebral bone mass and fragility fracture incidence suggests that there are mechanisms contributing to vertebral fracture independent of bone mass. These data highlight the importance of studying alterations to the bone matrix material properties and the activity of bone cells responsible for maintaining that matrix in T2D.

The hyperglycemic state in T2D contributes to the formation and accumulation of advanced glycation end-products (AGEs). The accumulation of AGEs impairs bone biomechanics via increasing collagen cross-linking and is a potential mechanism contributing to T2D skeletal fragility. AGEs not only directly alter the bone matrix, but they can have a negative effect on bone cells by activating the receptor for advanced glycation end-products (RAGE) which upregulates inflammatory pathways. The role of RAGE signaling in bone homeostasis and the control of bone strength remains relatively unknown. RAGE signaling and AGE accumulation may disrupt bone homeostasis and impair bone mechanics by altering bone cell function. Our hypothesis is that targeting RAGE will be a viable approach to restore bone cell function and rescue the mechanical deficits in bone observed in AGE-enriched pathologies like T2D.

This dissertation aims to elucidate the role of RAGE signaling in bone homeostasis and matrix mechanics under type 2 diabetic conditions. This was addressed by the completion of three specific aims. First, we evaluated whole bone mechanics, morphology, and AGE concentration in a mouse model of T2D to determine how those factors would be altered when we ablate RAGE signaling. As expected, with T2D bone had increased AGE concentration and impaired mechanical properties, some of these impairments were improved with the ablation of RAGE signaling. The second aim of this dissertation focuses on the cancellous bone matrix and characterizes bone cell activity, osteocyte density, and bone material properties in T2D mice with and without RAGE signaling. Here we showed that RAGE ablation improved matrix mechanics in T2D bone and osteocyte lacunar density.

Finally, the third aim hopes to translate the prior results to a clinically relevant model. Here we determined if a RAGE inhibition therapy could recapitulate the changes to the bone cell activity and matrix mechanics seen in the genetic model of RAGE ablation. RAGE inhibition resulted in similar matrix mechanical alterations to the genetic RAGE ablation model and there were improvements in longitudinal bone homeostasis. With the completion of these aims we have uncovered that bone matrix mechanics in T2D is at least partially controlled by RAGE signaling and warrants further research as a therapeutic approach for T2D bone fragility.

Dissertation Examination Committee:

Prof. Simon Tang, Chair
Prof. Mikhail Berezin

Prof. Katharine Flores
Prof. Lori Setton
Prof. Matthew Silva