Gla-Rich Protein Is a Novel Vitamin K-Dependent Protein Present in Serum That Accumulates at Sites of Pathological Calcifications

Abstract

Mineralization of soft tissues is an abnormal process that occurs in any body tissue and can greatly increase morbidity and mortality. Vitamin K-dependent (VKD) proteins play a crucial role in these processes; matrix Gla protein is considered one of the most relevant physiological inhibitors of soft tissue calcification know to date. Several studies have suggested that other , still unknown , VKD proteins might also be involved in soft tissue calcification pathologies. We have recently identified in sturgeon a new VKD protein , Gla-rich protein (GRP) , which contains the highest ratio between number of Gla residues and size of the mature protein so far identified. Although mainly expressed in cartilaginous tissues of sturgeon , in rat GRP is present in both cartilage and bone. We now show that GRP is a circulating protein that is also expressed and accumulated in soft tissues of rats and humans , including the skin and vascular system in which, when affected by pathological calcifications , GRP accumulates at high levels at sites of mineral deposition , indicating an association with calcification processes. The high number of Gla residues and consequent mineral binding affinity properties strongly suggest that GRP may directly influence mineral formation , thereby playing a role in processes involving connective tissue mineralization. (Am J Pathol

Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone

“…This highly conserved protein may be involved in the negative control of osteogenic differentiation of osteochondrogenic precursor cells in peripheral zones of fetal cartilage and at the cartilagebone interface as well as in the early phase of chondrocyte differentiation [14,15]. More recently, the UCMA/GRP protein was suggested to directly influence mineral formation and to play a role in processes involving soft tissue mineralization and abnormal calcification in the vascular system [16]. Investigation for alternatively spliced transcripts of UCMA/GRP in mice led to the identification of 4 isoforms, two of them probably secreted and two others reported to form aggregates in a structure similar to aggresome, an organelle where aggregated proteins are stored or degraded by autophagy [17].…”

Association between circulating vitamin K1 and coronary calcium progression in community-dwelling adults: the Multi-Ethnic Study of Atherosclerosis

“…It has been suggested that a reduction in the functional (carboxylated) MGP, rather than the amount of total MGP, may increase risk of vascular calcification (7). In addition to MGP, other vitamin K-dependent proteins in cardiovascular tissue, such as the gla-rich protein, may also influence atherosclerosis progression (8).…”

The role of carbonic anhydrase in the pathogenesis of vascular calcification in humans

“…In patients with chronic kidney disease, GRP is highly accumulated at sites of medial calcification, where the protein can be detected both inside the smooth muscle cells and in the extracellular matrix, in contrast with its almost absence in noncalcified areas [82]. GRP has been identified in other soft-tissue calcifications, such as skin calcification in dermatomyositis with calcinosis, invasive ductal carcinoma samples that include microcalcifications, and pseudoxanthoma elasticum where GRP co-localizes with mineral deposits [82].…”