The Role of Non-Collagenous Proteins, in Particular, Osteocalcin and Osteopontin, in the Determination of Bone Matrix Quality.

摘要

The mechanical integrity of bone is determined by bone mineral density (BMD), bone architecture and bone quality. Clinically, bone mass (measured as BMD) has been a dominant predictor of fracture risk. However, recent research has emphasized on the role of bone matrix quality in determining the propensity of bone to fracture. Bone quality encompasses the quality of the organic (collagen and non-collagenous proteins) and mineral components of bone. Within the scope of this work, it is shown that alterations within the organic component of bone like collagen and non-collagenous proteins cause ultrastructural changes in bone matrix. These changes result in compromised material organization and quality.;Collagen is the principal organic component in bone's matrix. Non-enzymatic glycation (NEG) induces post-translational modifications in collagen through the formation of advanced glycation end-products (AGEs) and alters the quality of bone material. To study NEG, in vitro approaches using atomic force microscopy and spectroscopy were adopted. In this study, results indicate that AGEs reduce collagen fibril diameter and energy dissipation characteristics. To corroborate these findings in bone, a study on Receptor for AGEs (RAGE) knock-out mice bones was conducted. The results support the role of glycation as a determinant of collagen quality and fracture toughness of bone matrix.;Non-collagenous proteins (NCP) like osteocalcin and osteopontin form a smaller fraction of bone's organic material. While osteocalcin binds strongly to bone mineral, osteopontin has been described as `bone glue'. Both are associated with bone mineral. The structural and mechanical properties of four genotypes; wild type (WT), osteocalcin deficient (OC-/-), osteopontin deficient (OPN-/-) and OC-OPN-/- or double knock-out mouse model were investigated in this study. Results show that OC and OPN regulate bone structure and mechanical competency—two vital characteristics of the vertebrate skeleton. They also complemented each other in determining bone length. In contrast to their synergistic role in bone size, they were inter-dependent in the maintenance of matrix quality. These findings highlight that OC and OPN function in both independent and dependent ways to regulate various aspects of the skeleton. Using small angle x-ray scattering and wavelength dispersive spectroscopy, this work also shows that OC and OPN play key roles in the regulation of bone mineral crystal size, morphology, organization and mineral composition, thereby regulating bone matrix quality.