Structural role of osteocalcin and its modification in bone fracture
Abstract
Osteocalcin (OC), an abundant non-collagenous protein in bone extracellular matrix, plays a vital role in both its biological and mechanical function. OC undergoes post-translational modification, such as glycation; however, it remains unknown whether glycation of OC affects bone's resistance to fracture. Here, for the first time, we demonstrate the formation of pentosidine, an advanced glycation end-product (AGE) cross-link on mouse OC analyzed by ultra-performance liquid chromatography. Next, we establish that the presence of OC in mouse bone matrix is associated with lower interlamellar separation (distance) and thicker bridges spanning the lamellae, both of which are critical for maintaining bone's structural integrity. Furthermore, to determine the impact of modification of OC by glycation on bone toughness, we glycated bone samples in vitro from wild-type (WT) and osteocalcin deficient (Oc−/−) mice, and compared the differences in total fluorescent AGEs and fracture toughness between the Oc−/− glycated and control mouse bones and the WT glycated and control mouse bones. We determined that glycation resulted in significantly higher AGEs in WT compared to Oc−/− mouse bones (delta-WT > delta-OC, p = 0.025). This observed change corresponded to a significant decrease in fracture toughness between WT and Oc−/− mice (delta-WT vs delta-OC, p = 0.018). Thus, we propose a molecular deformation and fracture mechanics model that corroborates our experimental findings and provides…
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