Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women

Abstract

Osteocalcin, also called bone gla protein, is a unique noncollagenous protein of the extracellular matrix of bone that circulates in blood. Oseteocalcin contains three residues of the vitamin K-dependent gamma-carboxyglutamic acid (gla) responsible for the affinity of osteocalcin for bone mineral. In animals treated with the vitamin K antagonist warfarin, the osteocalcin content of bone is markedly reduced and the fraction of osteocalcin released into the circulation is increased. Most studies have shown that osteocalcin increases with aging in women, reflecting an increase in bone turnover, especially after the menopause. To determine if this increase in osteocalcin could be associated with impaired carboxylation, we measured total and noncarboxylated osteocalcin in the serum of 72 women of various ages: 22 premenopausal (31 +/- 7 years old), 20 early postmenopausal (54 +/- 3 years), and 30 elderly women (85 +/- 8 years). As previously reported, total serum osteocalcin was significantly increased in early postmenopausal and elderly women. Noncarboxylated serum osteocalcin was slightly increased in early postmenopausal women (0.95 +/- 0.4 versus 0.65 +/- 0.5 ng/ml in premenopausal women), markedly elevated in elderly women (1.59 +/- 1.1 ng/ml, p less than 0.001), and correlated with age (r = 0.47, p less than 0.001). Elderly women had values of the same magnitude as in 10 patients on chronic warfarin therapy (1.94 +/- 1.1 ng/ml). As a consequence, the increase in carboxylated serum osteocalcin was significant in early postmenopausal women but not in elderly women. Serum levels of vitamin K1 and of menaquinones 6, 7, and 8 were measured in some of the young and elderly women.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants and Correlates of Serum Undercarboxylated Osteocalcin

“…The increase in serum iOC in women over the age of 50 in our study is consistent with the literature [7,18,22,25,26] . However, we did not find distinct differences in ucOC when comparing pre-and postmenopausal women as observed in other studies [7,20,27,28] .…”

Response of Serum Carboxylated and Undercarboxylated Osteocalcin to Risedronate Monotherapy and Combined Therapy with Vitamin K2 in Corticosteroid-Treated Patients: A Pilot Study

“…Since a part of the OC enters the bloodstream, the serum OC concentration is used as a marker of bone forma-tion (16,17 (18)(19)(20)(21) and that a high serum concentration of ucOC is related to the risk of fracture in elderly women or osteoporotic patients (22)(23)(24)(25)(26) Another striking finding in this study is that serum concentrations of OC and ucOC follow a very similar time course (27). The precise turnover of OC and ucOC in human serum has not been reported in the literature, although a study in rat models reported that one-half of the administered bone Gla protein may be cleared from serum in less than 5 minutes (17).…”

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

“…The presence of the three g carboxyglutamic acid residues is critical for the structure and function of OC in the fully carboxylated state allowing the binding of OC to hydroxyapatite (HA) with a high affinity, regulating the maturation of bone mineral (Hauschka & Wians 1989. However, OC also exists in the general circulation in fully carboxylated, partially carboxylated and completely uncarboxylated forms (Plantalech et al 1991, Cairns & Price 1994, Vergnaud et al 1997, Schilling et al 2005, Ferron et al 2010a. On the basis of results from human and rodent studies, serum OC concentrations have been correlated with bone formation and osteoblast number, thus being used as a serum marker of bone formation (Brown et al 1984;reviewed in Gundberg et al (2012)).…”