title: Targeting osteoblastic casein kinase-2 interacting protein-1 to enhance Smad-dependent BMP signaling and reverse bone formation reduction in glucocorticoid-induced osteoporosis.
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.
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Integrated Bioinfomedicine &Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen, China.|School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Department of Orthopaedics, Xi'an Third Hospital, Xi'an, China.|Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Lu
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Integrated Bioinfomedicine &Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen, China.|School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Xiaohao
authors.initials: X
authors.lastname: Wu
authors.affiliation: School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Zongkang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Integrated Bioinfomedicine &Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen, China.
authors.forename: Baosheng
authors.initials: B
authors.lastname: Guo
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Integrated Bioinfomedicine &Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen, China.
authors.forename: Defang
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Integrated Bioinfomedicine &Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liang
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Integrated Bioinfomedicine &Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Dang
authors.affiliation: Department of Orthopaedics and Traumatology, Bao'an Hospital Affiliated to Southern Medical University &Shenzhen 8th People Hospital, Shenzhen, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Spine Surgery, Shenzhen People's Hospital, Ji Nan University Second College of Medicine, Shenzhen, China.
authors.forename: Songlin
authors.initials: S
authors.lastname: Peng
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Integrated Bioinfomedicine &Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen, China.|School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.affiliation: School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Baoting
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Integrated Bioinfomedicine &Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005938:Glucocorticoids / Q000633:toxicity; D006801:Humans; D051379:Mice; D010012:Osteogenesis / Q000235:genetics*; D010024:Osteoporosis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051898:Smad1 Protein / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D005938:Glucocorticoids; D034741:RNA, Small Interfering; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; C000620556:PLEKHO1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins