Clinical potential of undercarboxylated osteocalcin in metabolic and neurodegenerative diseases: From biomarker to therapeutic target

Osteocalcin (OCN), a non-collagenous protein synthesized by osteoblasts, serves as both a critical factor in bone mineralization and an essential endocrine hormone in metabolic regulation. Beyond its skeletal functions, OCN operates as a crucial endocrine hormone involved in multiple physiological processes. Its influence extends to adipose tissue, the pancreas, skeletal muscle, and the central nervous system, contributing to glucose homeostasis and lipid metabolism. OCN demonstrates significant clinical applications across various pathological conditions. Undercarboxylated osteocalcin (Glu-OCN), a hormonally active form of osteocalcin, plays a pivotal role in various metabolic processes. This review examines Glu-OCN’s roles in diabetes, osteoporosis (OP), and Alzheimer’s disease and its broader impact on conditions such as nonalcoholic fatty liver disease (NAFLD) and depression, highlighting its significance in metabolic and neurodegenerative disorders. Through vitamin K-dependent carboxylation, OCN exists in multiple forms: noncarboxylated, carboxylated (Gla-OCN), and Glu-OCN, alongside bicarboxylated and tricarboxylated intermediate states. Each form exhibits distinct conformational properties and physiological functions, which are essential for various biological processes in human health.

In diabetic patients, OCN tends to rise in tandem with the progression of renal function, while patients with NAFLD exhibit significantly reduced OCN levels that inversely correlate with hepatic steatosis severity. Moreover, decreased serum OCN has been linked to increased Alzheimer’s disease (AD) risk, potentially via pathways modulating cholesterol metabolism and fasting blood glucose. This review summarizes and evaluates current researches on the biochemical pathways mediated by Glu-OCN, discussing its potential clinical applications as a diagnostic and therapeutic functions.