Biochemical characterization of a disease-causing human osteoprotegerin variant

Recently, a human mutation of OPG was identified to be associated with familial forms of osteoarthritis. This missense mutation (c.1205A =  > T; p.Stop402Leu) occurs on the stop codon of OPG, which results in a 19-residue appendage to the C-terminus (OPG +19 ). The biochemical consequence of this...

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Bibliographic Details
Published in:Scientific reports 2022-09, Vol.12 (1), p.15279-12, Article 15279
Main Authors: Luo, Yin, Li, Miaomiao, Xu, Ding
Format: Article
Language:English
Subjects:
631/45/612
631/80/304
Affinity chromatography
Apoptosis
C-Terminus
Cartilage
Cartilage diseases
Cell surface
Chondrocytes
Chondrocytes - metabolism
Chromatography
Heparan sulfate
Heparin
Heparitin Sulfate - metabolism
Homeostasis
Humanities and Social Sciences
Humans
Mineralization
Missense mutation
multidisciplinary
Mutants
Mutation
Oligomerization
Osteoarthritis
Osteoclastogenesis
Osteoprotegerin
Osteoprotegerin - chemistry
Osteoprotegerin - genetics
Osteoprotegerin - metabolism
Science
Science (multidisciplinary)
Stop codon
TNF-Related Apoptosis-Inducing Ligand - metabolism
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Summary:Recently, a human mutation of OPG was identified to be associated with familial forms of osteoarthritis. This missense mutation (c.1205A =  > T; p.Stop402Leu) occurs on the stop codon of OPG, which results in a 19-residue appendage to the C-terminus (OPG +19 ). The biochemical consequence of this unusual sequence alteration remains unknown. Here we expressed OPG +19 in 293 cells and the mutant OPG was purified to homogeneity by heparin affinity chromatography and size exclusion chromatography. We found that in sharp contrast to wildtype OPG, which mainly exists in dimeric form, OPG +19 had a strong tendency to form higher-order oligomers. To our surprise, the hyper-oligomerization of OPG +19 had no impact on how it binds cell surface heparan sulfate, how it inhibits RANKL-induced osteoclastogenesis and TRAIL-induced chondrocytes apoptosis. Our data suggest that in biological contexts where OPG is known to play a role, OPG +19 functions equivalently as wildtype OPG. The disease-causing mechanism of OPG +19 likely involves an unknown function of OPG in cartilage homeostasis and mineralization. By demonstrating the biochemical nature of this disease-causing OPG mutant, our study will likely help elucidating the biological roles of OPG in cartilage biology.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-19522-9