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Insights into the association of G la‐rich protein and osteoarthritis, novel splice variants and γ‐carboxylation status
Author(s) -
Rafael Marta S.,
Cavaco Sofia,
Viegas Carla S. B.,
Santos Sofia,
Ramos Acácio,
Willems Brecht A. G.,
Herfs Marjolein,
Theuwissen Elke,
Vermeer Cees,
Simes Dina C.
Publication year - 2014
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201300941
Subject(s) - osteoarthritis , calcification , cartilage , splice , hydroxyproline , gene isoform , alternative splicing , ectopic calcification , ectopic expression , biology , calcitonin , endocrinology , chemistry , medicine , microbiology and biotechnology , gene , biochemistry , pathology , anatomy , alternative medicine
Scope Gla‐rich protein ( GRP ) is a vitamin K dependent protein, characterized by a high density of γ‐carboxylated G lu residues, shown to accumulate in mouse and sturgeon cartilage and at sites of skin and vascular calcification in humans. Therefore, we investigated the involvement of GRP in pathological calcification in osteoarthritis ( OA ). Methods and results Comparative analysis of GRP patterning at transcriptional and translational levels was performed between controls and OA patients. Using a RT‐PCR strategy we unveiled two novel splice variants in human— GRP ‐F5 and F6—potentially characterized by the loss of full γ‐carboxylation and secretion functional motifs. GRP ‐F1 is shown to be the predominant splice variant expressed in mouse and human adult tissues, particularly in OA cartilage, while an overexpressing human cell model points it as the major γ‐carboxylated isoform. Using validated conformational antibodies detecting carboxylated or undercarboxylated GRP (c/uc GRP ), we have demonstrated c GRP accumulation in controls, whereas uc GRP was the predominant form in OA ‐affected tissues, colocalizing at sites of ectopic calcification. Conclusion Overall, our results indicate the predominance of GRP ‐ F 1, and a clear association of uc GRP with OA cartilage and synovial membrane. Levels of vitamin K should be further assessed in these patients to determine its potential therapeutic use as a supplement in OA treatment.