Protein S together with two other Gla proteins, osteocalcin (OC; or bone Gla protein) and matrix Gla protein (MGP), play a variety of only partly understood roles in bone and other mineralized tissues. Of these proteins, only OC is produced solely and specifically by mineralized tissue, whereas the other two (or at least their mRNA templates) are more widespread and occur also in soft tissues.
OC is synthesized specifically by osteoblasts and odontoblasts, and it accounts for ca. 15-20% of the noncollagen protein of the bone matrix. Approximately 20% is secreted into blood plasma, where it has no obvious function, but it has frequently been measured as an index of bone-forming (osteblastic) activity, and is present in increased amounts in plasma of people with certain bone diseases and of young infants. It is a small protein, MW 5700, with just three Gla residues. Unlike the blood coagulation Gla proteins, which in most people not severely vitamin K deficient and not vitamin K antagonist treated are almost completely carboxy-lated, circulating OC is at least 5-10% undercarboxy-lated in many population groups, as measured by assays that depend on the affinity of the undercarboxylated form for hydroxyapatite or a specific ELISA assay for the undercarboxylated form. Since vitamin K supplements can reduce its degree of undercarboxylation in many people, it has been proposed as a new and highly sensitive functional test of vitamin K status in man.
Despite the growing level of interest in its practical use as a status index, our understanding of the essential function of OC remains incomplete. Its affinity for calcium is less strong than that of the larger Gla proteins, but it binds avidly to hydroxyapatite and is chemotactic for osteoclasts and their progenitors. Moreover, it can enhance the differentiation of osteo-clast progenitor cells in culture, which has been interpreted as implying a possible role in bone resorption. Transgenic mice that lack the gene for OC have increased bone mass, despite an increased number of osteoclasts. In humans, however, underhydroxyla-tion of OC especially in postmenopausal women has been linked to low vitamin K intakes, reduced bone mineral density, and increased risk of fracture. Intervention with high-dose MK-4, mainly in Japan, has been reported to improve bone mineral density and decrease fracture risk. Although a single study in the United Kingdom suggested that a combination of vitamin K1 and vitamin D supplements may benefit bone mineral density in postmenopausal women, considerably more research is needed in this area. The separate roles of OC and other vitamin K-dependent proteins also need to be clarified.
The second vitamin K-dependent Gla protein in bone, MGP, has a MW of 9600 and five Gla residues and is highly insoluble. Unlike OC, it is also found in cartilage, and, significantly, its mRNA occurs in several soft tissues including artery walls. Its synthesis is modulated by 1,25-dihydroxy vitamin D and by retinoic acid. Mice lacking the gene for MGP quickly developed calcified arteries and died of aortic rupture before 2 months of age. For this reason, MGP is believed to antagonize the pathological calcification of soft tissues and thus to protect them. The absence of MGP also led to inappropriate calcification of growth plate cartilage, reduced growth, osteopenia, and fracture in the MGP gene knockout mice. In humans, defects in the MGP gene are associated with Keutel's syndrome and chondroplasia punctata, in which cartilage calcification is abnormal. Similar abnormalities have been observed in infants whose mothers were treated with warfarin during the first trimester of pregnancy. In one study, low vitamin K intake was associated with atherosclerotic calcification of the aorta in postmenopausal women. Also, circulating MGP levels were found to be raised in severe atherosclerosis and in type 1 diabetes in humans. A specific immunoassay for MGP has been developed that should assist further research on this potentially important regulatory protein.
The third bone-associated Gla protein, protein S, is also involved with blood clotting. It is synthesized by osteoblast-like and osteblastoma cells in culture, and it has been detected in bone matrix. It is also synthesized by hepatocytes, megakaryocytes, and endothelial cells. Children with an inborn deficiency of it developed osteopenia and bone lesions; however, its precise functional role is unknown.
All three bone Gla proteins (and probably most other Gla proteins) have 'leader' or 'pre'-peptides when first formed on the endoplasmic reticulum (ER) that are required for translocation across the ER and are removed during this process. OC, protein S, and most other Gla proteins also have a pro-peptide sequence that is removed during secretion and that directs the action of the carboxylase enzyme before secretion. MGP differs from the other Gla proteins in that its carboxylase recognition sequence is not removed; instead, only a short (five-residue) carboxy-terminal sequence is removed from it. All known mammalian Gla proteins contain the characteristic amino acid sequence
Gla-X-X-X-Gla-X-Cys, where X represents an undefined amino acid. If vitamin K is in short supply or antagonized, certain Gla residues escape gamma-gluta-myl formation more than others. Thus, in a study of OC, the Glu residue at position 17 was typically only 67% carboxylated, that at position 21 was 88% carboxy-lated, and that at position 24 was 93% carboxylated.
Surprisingly, in a meta-analysis of studies on warfarin-treated adult patients, no evidence of any increase in bone disorders was found.
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