[[The]] role of extra-cellular matrix proteins and post-translational modifications on bone fracture

Abstract

Finally, the contribution of PTMs to bone fracture in a type-II diabetic model was evaluated. Obesity-induced diabetes resulted in an increase in the amount of non-enzymatic cross-links and an associated reduction in bone propagation toughness. This project provides an understanding of the role of bone matrix proteins and their modifications on bone size, shape, strength, and fracture.

Osteocalcin (OC) and osteopontin (OPN) are major NCPs in bone matrix. They exhibit multifunctional roles that are critical in the determination of bone quality and bone’s structural integrity against fracture. In this study, using genetically modified mice, we show that OC and OPN synergistically influence bone size, shape and strength. Post-translational modifications (PTMs) of these bone matrix proteins can be detrimental to bone quality. Protocols developed for in-vitro PTMs of whole bone were applied to OC and OPN knockout mice and bone material properties assessed using fracture mechanics. The results show that glycated OC contributes to loss of bone toughness and phosphorylation of OPN increases bone fracture resistance.

Bone is a complex structural material that deteriorates in quality with age and disease. As a result, bone is unable to perform its critical mechanical function leading to fracture. Clinically, diagnosis of osteoporosis and the susceptibility to fracture are determined by Bone Mineral Density (BMD). However, multiple factors in addition to BMD contribute to the fracture resistance of bone such as the quality and composition of bone’s primary constituents. These constituents are hydroxyapatite mineral, type I collagen and non-collagenous proteins (NCPs). Consequently, the spatial arrangement of these nanoscale elements determines the mechanical properties of bone. Nevertheless, the contribution of NCPs in the determination of bone quality and fracture remains largely undefined.