Effects of the TNFRSF11B Mutation Associated With Calcium Pyrophosphate Deposition Disease in Osteoclastogenesis in a Murine Model.

Autor: Mitton-Fitzgerald E; Medical College of Wisconsin and Milwaukee VA Medical Center, Milwaukee., Gohr CM; Medical College of Wisconsin and Milwaukee VA Medical Center, Milwaukee., Williams CJ; Cooper Medical School of Rowan University, Camden, New Jersey., Ortiz A; Cooper Medical School of Rowan University, Camden, New Jersey., Mbalaviele G; Washington University School of Medicine, St. Louis, Missouri., Rosenthal AK; Medical College of Wisconsin and Milwaukee VA Medical Center, Milwaukee.
Jazyk: angličtina
Zdroj: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2021 Aug; Vol. 73 (8), pp. 1543-1549. Date of Electronic Publication: 2021 Jun 08.
DOI: 10.1002/art.41678
Abstrakt: Objective: The gene TNFRSF11B encodes for osteoprotegerin (OPG) and was recently identified as the CCAL1 locus associated with familial calcium pyrophosphate deposition disease (CPDD). While the CCAL1 OPG mutation (OPG-XL) was originally believed to be a gain-of-function mutation, loss of OPG activity causes arthritis-associated osteolysis in mice, which is likely related to excess subchondral osteoclast formation and/or activity. The purpose of the present study was to further explore the effect of OPG-XL in osteoclastogenesis.
Methods: The effects of recombinant OPG-XL and wild-type (WT) OPG were determined in monoculture and coculture models of RANKL-induced osteoclastogenesis. The effects of OPG-XL on osteoclast survival as well as on TRAIL-induced apoptosis were determined using standard in vitro assays and compared to WT OPG. The ability of OPG-XL and WT OPG to bind to osteoblasts was measured with enzyme-linked immunosorbent assay and flow cytometry using the osteoblastic MC3T3-E1 cell line.
Results: OPG-XL was less effective than WT OPG at blocking RANKL-induced osteoclastogenesis in monoculture and coculture models. Osteoclast survival and inhibition of TRAIL-induced apoptosis were similar in the presence of OPG-XL and WT OPG. Compared to WT OPG, considerably less OPG-XL bound to cells.
Conclusion: These findings indicate that OPG-XL is a loss-of-function mutation as it relates to RANKL-mediated osteoclastogenesis, and thus may permit increased osteoclast numbers and heightened bone turnover. Further studies are necessary to demonstrate how this mutation contributes to arthritis in individuals carrying this mutation.
(© 2021, American College of Rheumatology.)
Databáze: MEDLINE
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