Osteocalcin (OTCC)
Osteocalcin (OTCC)
Osteocalcin (OTCC) is a small, non-collagenous protein hormone produced exclusively by osteoblasts, the bone-forming cells. It is one of the most abundant non-collagenous proteins in bone and is also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP)752.
Structure and Synthesis
- Osteocalcin is encoded by the BGLAP gene in humans and consists of 49 amino acids75.
- Its synthesis is vitamin K-dependent, as vitamin K is required for the gamma-carboxylation of specific glutamic acid residues. This carboxylation allows osteocalcin to bind calcium and become incorporated into the bone matrix57.
- The carboxylated form is primarily found in bone, while the uncarboxylated form can act as a hormone in the bloodstream71.
Functions
Bone Marker and Bone Quality
- Osteocalcin has traditionally been used as a sensitive and specific marker of bone formation and turnover, reflecting osteoblastic activity28.
- While initially thought to be important for bone mineralization, studies in mice have shown that osteocalcin depletion has only minor effects on bone density and mineralization. Instead, osteocalcin appears to influence bone quality by regulating the alignment of apatite crystals with collagen fibrils, which affects bone strength68.
Endocrine (Hormonal) Roles
- Glucose Metabolism: Uncarboxylated osteocalcin acts as a hormone, influencing insulin secretion from the pancreas and increasing insulin sensitivity in adipose tissue by stimulating adiponectin release137. Lower levels of osteocalcin are associated with type 2 diabetes and metabolic syndrome in humans4.
- Male Fertility: Osteocalcin stimulates testosterone production in Leydig cells of the testes, affecting male fertility17.
- Muscle Function and Adaptation: It promotes energy utilization in muscle, favoring exercise capacity17.
- Neuronal Development and Cognition: Osteocalcin influences brain development and cognitive functions such as memory, with animal studies suggesting it may help rescue memory loss and defective neuronal development17.
- Acute Stress Response: Osteocalcin is rapidly released during acute stress, contributing to the fight-or-flight response7.
Receptors
- Osteocalcin exerts its hormonal effects through specific receptors, primarily GPRC6A (in pancreas and testes) and GPR158 (in the brain)174.
Clinical Significance
- Marker for Bone Formation: Osteocalcin is widely used as a biomarker for bone turnover in clinical practice, aiding in the diagnosis and monitoring of metabolic bone diseases such as osteoporosis, Paget’s disease, and renal osteodystrophy2.
- Metabolic Health: Lower serum osteocalcin levels are linked to impaired glucose metabolism and increased cardiovascular risk4.
- Exercise: Physical activity increases serum osteocalcin, which correlates with improved bone formation and glucose metabolism68.
Controversies and Ongoing Research
- Some recent animal studies challenge earlier findings, suggesting that while osteocalcin regulates bone quality, its role as a systemic hormone affecting glucose metabolism, testosterone synthesis, and muscle mass may not be as significant as previously thought68. More research is needed to clarify its roles in humans.
Summary Table
| Aspect | Details |
|---|---|
| Produced by | Osteoblasts |
| Main forms | Carboxylated (bone matrix), uncarboxylated (hormonal functions) |
| Key functions | Marker of bone formation; regulates bone quality; possible endocrine roles |
| Endocrine effects | Glucose metabolism, male fertility, muscle function, brain development (mainly in mice) |
| Clinical use | Biomarker for bone turnover and metabolic bone diseases |
| Receptors | GPRC6A, GPR158 |
Osteocalcin is a bone-derived protein with established use as a marker of bone formation and emerging roles as a hormone influencing metabolism, fertility, muscle, and brain function-though some of these roles are still under investigation, especially in humans147.
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Key References with DOI Links
New Insights into the Biology of Osteocalcin – PMC1
Osteocalcin-A Versatile Bone-Derived Hormone – Frontiers in Endocrinology2
Osteocalcin | Arteriosclerosis, Thrombosis, and Vascular Biology5
An Investigation Into the Role of Osteocalcin in Human Arterial Smooth Muscle Cell Calcification – Frontiers in Endocrinology6
Osteocalcin, Vascular Calcification, and Atherosclerosis: A Systematic Review and Meta-analysis – Frontiers in Endocrinology7
