title: Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging.
abstract: Emerging evidence indicates that the dysregulation of protein ubiquitination plays a crucial role in aging-associated diseases. Smad-dependent canonical BMP signaling pathway is indispensable for osteoblastic bone formation, which could be disrupted by the ubiquitination and subsequent proteasomal degradation of Smad1/5, the key molecules for BMP signaling transduction. However, whether the dysregulation of Smad1/5 ubiquitination and disrupted BMP signaling pathway is responsible for the age-related bone formation reduction is still underexplored. Pleckstrin homology domain-containing family O member 1 (PLEKHO1) is a previously identified ubiquitination-related molecule that could specifically target the linker region between the WW domains of Smurf1 to promote the ubiquitination of Smad1/5. Here, we found an age-related increase in the expression of PLEKHO1 in bone specimens from either fractured patients or aging rodents, which was associated with the age-related reduction in Smad-dependent BMP signaling and bone formation. By genetic approach, we demonstrated that loss of Plekho1 in osteoblasts could promote the Smad-dependent BMP signaling and alleviated the age-related bone formation reduction. In addition, osteoblast-specific Smad1 overexpression had beneficial effect on bone formation during aging, which could be counteracted after overexpressing Plekho1 within osteoblasts. By pharmacological approach, we showed that osteoblast-targeted Plekho1 siRNA treatment could enhance Smad-dependent BMP signaling and promote bone formation in aging rodents. Taken together, it suggests that the increased PLEKHO1 could suppress Smad-dependent BMP signaling to inhibit bone formation during aging, indicating the translational potential of targeting PLEKHO1 in osteoblast as a novel bone anabolic strategy for reversing established osteoporosis during aging.
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 and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, 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.|Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, 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 and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, 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 and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, China.
authors.forename: Xiaohao
authors.initials: X
authors.lastname: Wu
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 and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, China.
authors.forename: Defang
authors.initials: D
authors.lastname: Li
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: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Zheng
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 and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Dang
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 and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: He
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, Chinajing, 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.|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.|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: School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Bao-Ting
authors.initials: BT
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 and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, China.
authors.forename: Aiping
authors.initials: A
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 and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.|Institute of Precision Medicine and Innovative Drug Discovery, Hong Kong Baptist University, Hong Kong SAR, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D009929:Organ Size; D009928:Organ Specificity; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D010052:Ovariectomy; D051381:Rats; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D047908:Intracellular Signaling Peptides and Proteins; C408877:PLEKHO1 protein, human; C000620556:PLEKHO1 protein, mouse; C000620534:PLEKHO1 protein, rat; D051785:Smad Proteins
keywords: BMP signaling; aging; osteoblast; osteoporosis