Effects of the TNFRSF11B Mutation Associated With Calcium Pyrophosphate Deposition Disease in Osteoclastogenesis in a Murine Model
| Autor: | Elizabeth Mitton-Fitzgerald, Ann K. Rosenthal, Amaryllis Ortiz, Charlene J. Williams, Claudia M. Gohr, Gabriel Mbalaviele |
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| Rok vydání: | 2021 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine medicine.medical_specialty Osteolysis Immunology Chondrocalcinosis Article Cell Line Bone remodeling Flow cytometry Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Rheumatology Osteoprotegerin Loss of Function Mutation Osteogenesis Osteoclast Internal medicine medicine Animals Immunology and Allergy 030203 arthritis & rheumatology medicine.diagnostic_test Calcium pyrophosphate medicine.disease Coculture Techniques Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Cell culture Apoptosis Bone Remodeling |
| Zdroj: | Arthritis Rheumatol |
| ISSN: | 2326-5205 2326-5191 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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