Definition
Osteocalcin (OC) is a 49 amino acid peptide found exclusively in bone tissue and is highly conserved among species. Circulating levels of human OC correlate with the skeletal isoenzyme of alkaline phosphatase and can be used as an index of bone formation. OC-fragments are released during osteoclastic bone resorption and that the quantification of specific age-modified OC fragments can provide an index of bone resorption.
Discovery
Osteocalcin was discovered by Price and co-workers in the year 1976 1. It is known that OC, the most abundant noncollagenous protein produced by osteoblasts, through the post-translational carboxylation process gains high affinity for mineral ions thus binding to hydroxyapatite 2. Data have shown that vitamin K1 insufficiency followed by higher levels of undercarboxylated OC leads to increased susceptibility to vertebral fracture independent from bone mineral density 3. Moreover, circulating levels of undercarboxylated OC comprise an indicator of risk for hip fracture4. Lee et al., 2007, demonstrated that uncarboxylated OC induces in vitro, the expression of insulin. Carboxylation of OC – triggered by vitamin K – was responsible for alterations in insulin response in the young male volunteers. They suggested osteocalcin's regulatory roles to include stimulating CyclinD1 and insulin expression in ß-cells and adiponectin expression in adipocytes. These results suggest that the skeleton should be considered to be an endocrine organ that regulates sugar homeostasis and energy metabolism 5.
Structural Characteristics
OC is a 49-residue polypeptide, synthesized as an 11kDa prepro-osteocalcin of 98 residues. This molecule consists of 3 parts, a 23-residue signal peptide that is cleaved during translation, a 26-residue polypeptide that targets the protein for carboxylation and the 49-residue mature peptide.
OC structure has been determined by X-ray crystallography, it reveals a negatively charged protein surface that places five calcium ions in positions complementary to those in hydroxyapatite, an important mineral component of bone. Using this recognition mechanism, osteocalcin could potentially modulate the crystal morphology and growth of hydroxyapatite. And in this complex, the carboxy terminus of osteocalcin, which promotes the adhesion of osteoblasts and osteoclastsin in bone replacement, is readily accessible 6.
Mode of Action
OC is a vitamin K- and D-dependent protein produced by osteoblasts, osteocytes and odontoblasts. It is deposited in extracellular bone matrix and is found in the serum. Serum OC, hydrolysed in the kidney and liver, is considered a specific marker of osteoblast activity and bone formation rate. It may be involved in regulation of osteoblast function, regulation of bone turnover and/or mineralization 7. The uncarboxylated OC regulated glucose homeostasis in Ptprv–/– mice, whilst only uncarboxylated OC induced the expression of insulin, ß-cell proliferation and expression of adiponectin in adipocytes, in co-culture assays 8. The role of OC in human metabolism suggests that levels of uncarboxylated OC tended to be lower – albeit not significantly – in normoglycemic insulin resistant as well as untreated type 2 diabetes mellitus (T2DM) patients compared with normoglycemic insulin sensitive patients, concluding that OC is independently related to insulin sensitivity and fasting glucose and these interactions are primarily due to the uncarboxylated form of OC 7.
Mode of Action
OC is a vitamin K- and D-dependent protein produced by osteoblasts, osteocytes and odontoblasts. It is deposited in extracellular bone matrix and is found in the serum. Serum OC, hydrolysed in the kidney and liver, is considered a specific marker of osteoblast activity and bone formation rate. It may be involved in regulation of osteoblast function, regulation of bone turnover and/or mineralization 7. The uncarboxylated OC regulated glucose homeostasis in Ptprv–/– mice, whilst only uncarboxylated OC induced the expression of insulin, ß-cell proliferation and expression of adiponectin in adipocytes, in co-culture assays 8. The role of OC in human metabolism suggests that levels of uncarboxylated OC tended to be lower – albeit not significantly – in normoglycemic insulin resistant as well as untreated type 2 diabetes mellitus (T2DM) patients compared with normoglycemic insulin sensitive patients, concluding that OC is independently related to insulin sensitivity and fasting glucose and these interactions are primarily due to the uncarboxylated form of OC 7.
References
1. Price PA, Otsuka AS, Poser JW, Kristponis J, Raman N (1976). Characterization of the gamma-carboxyglutamic acid-containing protein from bone. Proc Natl Acad Sci USA, 73:1447–1451.
2. Hauschka PV, Lian JB, Cole DE, Gundberg CM (1989). Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiological Reviews, 69:990–1047.
3. Tsugawa N, Shiraki M, Suhara Y, Kamao M, Ozaki R, Tanaka K, Okano T (2008). Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. Journal of Bone and Mineral Metabolism, 26: 79–85.
4. Seibel MJ, Robins SP, Bilezikian JP (1997). Serum undercarboxylated osteocalcin and the risk of hip fracture. Journal of Clinical Endocrinology and Metabolism, 82: 717–718.
5. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY (2007). Endocrine regulation of energy metabolism by the skeleton. Cell, 130: 456–469.
6. Hoang QQ, Sicheri F, Howard AJ, Yang DS (2003). Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature, 425:977-980.
7. Tsugawa N, Shiraki M, Suhara Y, Kamao M, Ozaki R, Tanaka K, Okano T (2008). Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. Journal of Bone and Mineral Metabolism, 26: 79–85.
8. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G (1997). Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature, 386:78–81.
9. Sakamoto N, Nishiike T, Iguchi H, Sakamoto K (2000). Possible effects of one week vitamin K (menaquinone-4) tablets intake on glucose tolerance in healthy young male volunteers with different descarboxy prothrombin levels. Clinical Nutrition, 19:259–263.
10. Kassi E, Papavassiliou AG (2008). A possible role of osteocalcin in the regulation of insulin secretion: human in vivo evidence. Journal of Endocrinology, 199:151-153.