Type 2 diabetes mellitus (T2D) is a condition that currently affects over 360 million people worldwide. Among these patients, there is a 3-fold increase in fracture risk compared to healthy adults. One of the factors thought to be associated with this increase in fracture risk is an accelerated accumulation of protein crosslinks known as Advanced Glycation End-Products (AGEs) in bone. AGEs disrupt bone’s collagen network and can deteriorate its mechanical properties, ultimately leading to the increase in skeletal fragility. However, the processes that occur between AGE accumulation and skeletal fragility are not fully understood. It is likely that one of the many mechanisms is that AGEs in T2D affect bone cell behavior, which impacts bone tissue quality and consequent mechanical behavior. Osteocyte bone cells respond to AGEs and hyperglycemic conditions by releasing extracellular signaling proteins which affect bone remodeling. Two key extracellular signaling proteins expressed by osteocytes are sclerostin and receptor activator of nuclear factor-кB ligand. An alteration in their expression by osteocytes grown in high glucose and/or high AGE environments may result in low bone turnover. This osteocytic response leads to poor bone tissue quality, and consequently, can deteriorate bone’s mechanical properties and increase skeletal fragility in T2D. As a result, osteocytes become an essential research candidate for solving the poorly understood links between T2D and skeletal fragility.

Our goal was to investigate the behaviors of a novel osteocyte cell line (Ocy454) in high sugar conditions as well as on glycation-induced AGE substrates, such as glycated collagen, in order to better understand the links between T2D and skeletal fragility. We used Ocy454 cells, which have a mature phenotype and serve as an appropriate model for measuring gene and protein expression in response to external environments. We hypothesized that osteocytes cultured in hyperglycemic and naturally induced AGE environments will have an increase in the expression of factors that disrupt bone remodeling and turnover. We found that hyperglycemic environments increase the expression of sclerostin, a signaling protein that supports the inhibition of bone formation. We also found that high sugar causes changes in the expression of RANKL, a signaling protein that supports bone degradation. Additionally, naturally induced AGEs were found to increase RANKL gene expression. These combined changes in osteocyte behavior due to T2D environments suggests that bone remodeling may be altered from a healthy physiological state. Disrupted bone remodeling may affect the overall quality of bone, leading it to be more susceptible to fracture. Ultimately, our work may provide information to design enhanced methodologies to help clinicians treat the high bone fracture risk associated with T2D patients.