Undercarboxylated osteocalcin emerges as a biomarker and therapeutic target in metabolic and neurodegenerative diseases
image: Carboxylation and decarboxylation dynamics of osteocalcin Glu-OCN is secreted by osteoblasts and then undergoes γ-carboxylation at glutamic acid residues at positions 17, 21, and 24, a reaction catalyzed by γ-glutamyl carboxylase (GGCX) in a vitamin K-dependent manner. The fully carboxylated form, Gla-OCN, is incorporated into the extracellular matrix(ECM) of bone tissue. During bone resorption, the acidic microenvironment facilitates the decarboxylation of Gla-OCN, converting it back to Glu-OCN, which is subsequently released into the systemic circulation. Glu-OCN: undercarboxylated osteocalcin; GGCX: γ-glutamyl carboxylase; Gla-OCN: noncarboxylated, carboxylated; ECM: extracellular matrix.
Credit: Ying-ying Ding, Yu-ying Yang, Li-hao Sun, Jian-min Liu, Bei Tao.
Osteocalcin (OCN), a protein produced by bone-forming cells, has traditionally been studied for its role in bone mineralization. In recent years, its undercarboxylated form (Glu-OCN) has gained attention as a key regulator of metabolic and neurological health. This review highlights Glu-OCN’s wide-ranging effects on glucose and lipid metabolism, bone density, and brain function, positioning it as both a diagnostic biomarker and potential therapeutic target.
In metabolic diseases, Glu-OCN influences insulin secretion, sensitivity, and energy metabolism through the GPRC6A signaling pathway. Clinical evidence shows that lower Glu-OCN levels correlate with obesity, diabetes, nonalcoholic fatty liver disease (NAFLD), and osteoporosis. Conversely, experimental studies reveal that Glu-OCN administration can improve glucose control, lipid metabolism, and bone health.
Beyond metabolism, Glu-OCN has been linked to cardiovascular and neurodegenerative conditions. Reduced levels are associated with atherosclerosis, vascular calcification, and cognitive decline. In Alzheimer’s disease, osteocalcin may protect neurons by enhancing energy metabolism, reducing inflammation, and stimulating neurotrophic factor release. Similarly, in depression, osteocalcin appears to regulate mood by crossing the blood-brain barrier and modulating neurotransmitter activity.
Despite promising findings, most studies remain cross-sectional or observational, limiting causal conclusions. Current detection methods also struggle to distinguish between OCN forms, complicating clinical application. Future advances in biomarker measurement and large-scale longitudinal studies will be essential for validating Glu-OCN’s role in early diagnosis, personalized treatment, and therapeutic monitoring.