Homocysteine as a Pathological Biomarker for Bone Disease

Abstract

In the last few decades, perturbation in methyl-group and homocysteine (Hcy) balance have emerged as independent risk factors in a number of pathological conditions including neurodegenerative disease, cardiovascular dysfunction, cancer development, autoimmune disease, and kidney disease. Recent studies report Hcy to be a newly recognized risk factor for osteoporosis. Elevated Hcy levels are known to modulate osteoclastgenesis by causing detrimental effects on bone via oxidative stress induced metalloproteinase-mediated extracellular matrix degradation and decrease in bone blood flow. Evidence from previous studies also suggests that the decreased chondrocytes mediated bone mineralization in chick limb-bud mesenchymal cells and during the gestational period of ossification in rat model. However, Hcy imbalance and its role in bone loss, regression in vascular invasion, and osteoporosis, are not clearly understood. More investigations are required to explore the complex interplay between Hcy imbalance and onset of bone disease progression. This article reviews the current body of knowledge on regulation of Hcy mediated oxidative stress and its role in bone remodeling, vascular blood flow and progression of bone disease. J. Cell. Physiol. 232: 2704-2709, 2017. © 2016 Wiley Periodicals, Inc.

Fig. 1

Schematic mechanism of homocysteine-mediated bone remodeling via oxidative stress. The increased homocysteine level elevates intracellular calcium by agonizing NMDA-RI. This in turn increases activation of calcium dependent calpain-I, which disrupts the mitochondrial membrane potential. Thus increasing reactive oxygen species (ROS) which further activates MMPs, resulting in matrix degradation. Increased homocysteine levels also induces apoptosis via ROS-mediated oxidative pathways which further switches off osteoblast activity and mineralization, by up regulating RANKL expression, leading to osteoporosis by reducing bone formation.

Fig. 2

Mechanism of homocysteine that contribute to the development of osteoporosis. Homocysteine level is associated with increased oxidative stress in bone microenvironment. Increased reactive oxygen species (ROS) induces osteoblast apoptosis thereby decreasing osteoblastgenesis. This increase in oxidative stress further reduces NO bioavailability, by producing superoxide anions ( ${\mathrm{O}}_2^{-}$), which could also decrease bone blood flow and possibly angiogenesis. The ROS generated by this process activates osteoclastgenesis, by monocyte fusion, further contributing to loss in bone density; leading to osteoporosis.