The TNFRSF11B mutation associated with calcium pyrophosphate deposition disease results in ineffective osteoclast suppression

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, loss of OPG activity causes arthritis-associated osteolysis in mice, likely related to excess subchondral osteoclast (OC) formation and/or activity. The purpose of this work was to further explore the effect of OPG-XL in osteoclastogenesis. The effects of recombinant OPG-XL and wild type OPG (wtOPG) were determined in monoculture and co-culture models of RANKL-induced osteoclastogenesis. The effects of OPG-XL on OC survival as well as on TRAIL-induced apoptosis were determined using standard in vitro assays and compared to wtOPG. The ability of OPG-XL and wtOPG to bind to osteoblasts was measured with ELISA and flow cytometry using the osteoblastic cell line MC3T3-E1. OPG-XL was less effective than wtOPG at blocking RANKL-induced osteoclastogenesis in monoculture and co-culture models. OC survival and inhibition of TRAIL-induced apoptosis were similar in the presence of OPG-XL and wtOPG. Compared to wtOPG, considerably less OPG-XL bound to cells. We show here that OPG-XL is a loss-of-function mutation as it relates to RANKL-mediated osteoclastogenesis and thus may permit increased OC number and heightened bone turnover. Further studies will be necessary to demonstrate how this mutation contributes to arthritis in individuals carrying this mutation.