Abstract
The underlying mechanism of the reduced bone formation during the development of glucocorticoid-induced osteoporosis (GIO) remains unclear. Here, we found that the highly expressed CKIP-1 together with lowly expressed total and phosphorylated Smad1/5 in bone samples was accompanied by either the reduced serum bone formation markers in GIO patients or the decreased bone formation in GIO mice. In vitro studies showed that the highly expressed CKIP-1 could promote Smad1 ubiquitination to suppress the Smad-dependent BMP signaling and inhibit osteogenic differentiation and mineral deposition in MC3T3-E1 cells during glucocorticoid treatment. Further, the reduced bone formation in GIO mice could not only be prevented by osteoblasts-specific Ckip-1 ablation, but also be attenuated after osteoblasts-specific Smad1 overexpression. Moreover, osteoblasts-targeting CKIP-1 siRNA treatment also attenuated the bone formation reduction in GIO mice. These study suggest that the highly expressed CKIP-1 in osteoblasts could suppress the Smad-dependent BMP signaling and contribute to the bone formation reduction in GIO. Targeting osteoblastic CKIP-1 would be a novel bone anabolic strategy for GIO patients.
Highlights
Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis with increased fracture risk[1,2]
We examined the effects of casein kinase-2 interacting protein-1 (CKIP-1) knock down by siRNA on osteogenic differentiation and mineral deposition in MC3T3-E1 cells treated with GC in vitro, the MC3T3-E1 cells were transfected with CKIP-1 siRNA encapsulated within Lipofectamine 2000 (RNAi Groups), non-sense siRNA encapsulated within
This is the first study to elucidate the role of ubiquitination-related molecule CKIP-1 within osteoblasts in regulating the Smad-dependent bone morphogenetic protein (BMP) and bone formation during the development of GIO
Summary
Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis with increased fracture risk[1,2]. Recent studies revealed that dexamethasone could significantly suppress the activation of Smad-dependent BMP signaling in osteoblastic cell lines[14,15], there is no direct evidence to show the involvement of CKIP-1 in regulating the BMP signaling pathway in osteoblasts during the development of GIO. We showed that osteoblasts-targeting CKIP-1 siRNA treatment could enhance the Smad-dependent BMP signaling and attenuate bone formation reduction in GIO mice. Together, these data suggest that targeting osteoblastic CKIP-1 could be a novel bone anabolic strategy for GIO patients
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