Dickkopf-1 (Dkk1) is a negative regulator of bone formation and bone mass and is deregulated in bone loss induced by arthritis and glucocorticoid (GC) exposure. However, the role of Dkk1 in these pathological processes is still unknown. Here, we used conditional Dkk1 knock-out mice to determine the role of Dkk1 produced by osteolineage cells in the development of arthritis and GC-induced bone loss. Osteoprogenitor (Osx-Cre)- and osteocyte (Dmp1-Cre)-specific knock-out mice and their Cre-negative controls were subjected to two arthritis models, K/BxN and antigen-induced arthritis. Disease induction and progression were assessed. GC-induced bone loss was induced in 25-week-old female mice by implanting prednisolone (7.5 mg) slow-release pellets for 4 weeks. Dkk1fl/fl ;Osx-Cre mice subjected to K/BxN arthritis showed mildly reduced disease severity with reduced infiltration of neutrophils and T cells into affected joints and reduced bone erosions compared with Cre-negative controls. Osteocyte-specific Dkk1 deletion did not affect disease severity or local bone erosions. However, systemic bone loss at the spine was less severe in both mouse lines. In contrast to arthritis, both lines were protected from GC-induced bone loss. Although the Cre-negative controls lost about 26% and 31% bone volume potentially caused by decreased bone formation, Cre-positive mice did not exhibit such alterations. Dkk-1 deficiency in osteolineage cells protects against GC-induced bone loss, whereas it had only minor effects in arthritis. Therefore, Dkk1 may be a promising therapeutic target especially for bone diseases in which inhibition of bone formation represents the predominant mechanism. © 2019 American Society for Bone and Mineral Research.
Keywords: CORTICOSTEROIDS; GENETIC ANIMAL MODELS; OSTEOIMMUNOLOGY; OSTEOPOROSIS; WNT/BETA-CATENIN/LRPS.
© 2019 American Society for Bone and Mineral Research.