TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease

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Wu, Mengrui¹; Chen, Guiqian^1,2; Li, Yi-Ping¹

TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease

Bone Res. 2016;4:16009

©2016 Sichuan University

Affiliations

¹Department of Pathology, University of Alabama at Birmingham, Birmingham, USA

²Department of neurology, Bruke Medical Research Institute, Weil Cornell Medicine of Cornell University, White Plains, USA
Abstract

Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling has fundamental roles in both embryonic skeletal development and postnatal bone homeostasis. TGF-βs and BMPs, acting on a tetrameric receptor complex, transduce signals to both the canonical Smad-dependent signaling pathway (that is, TGF-β/BMP ligands, receptors, and Smads) and the non-canonical-Smad-independent signaling pathway (that is, p38 mitogen-activated protein kinase/p38 MAPK) to regulate mesenchymal stem cell differentiation during skeletal development, bone formation and bone homeostasis. Both the Smad and p38 MAPK signaling pathways converge at transcription factors, for example, Runx2 to promote osteoblast differentiation and chondrocyte differentiation from mesenchymal precursor cells. TGF-β and BMP signaling is controlled by multiple factors, including the ubiquitin–proteasome system, epigenetic factors, and microRNA. Dysregulated TGF-β and BMP signaling result in a number of bone disorders in humans. Knockout or mutation of TGF-β and BMP signaling-related genes in mice leads to bone abnormalities of varying severity, which enable a better understanding of TGF-β/BMP signaling in bone and the signaling networks underlying osteoblast differentiation and bone formation. There is also crosstalk between TGF-β/BMP signaling and several critical cytokines’ signaling pathways (for example, Wnt, Hedgehog, Notch, PTHrP, and FGF) to coordinate osteogenesis, skeletal development, and bone homeostasis. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in osteoblast differentiation, chondrocyte differentiation, skeletal development, cartilage formation, bone formation, bone homeostasis, and related human bone diseases caused by the disruption of TGF-β/BMP signaling.
Links

DOI: 10.1038/boneres.2016.9

PubMed: 27563484

WoS: 000380797200001
History

Received: 2015-12-29

Revised: 2016-03-04

Accepted: 2016-03-07

Online: 2016-04-26

Cited Works (3)

Year	Entry
2006	Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. May 2006;38(5):525-528.
2006	Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet. December 2006;38(12):1424-1429.
2012	Long F. Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol. January 2012;13(1):27-38.

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2020	Lukač N, Katavić V, Novak S, Šućur A, Filipović M, Kalajzić I, Grčević D, Kovačić N. What do we know about bone morphogenetic proteins and osteochondroprogenitors in inflammatory conditions? Bone. August 2020;137:115403.
2020	Wang W, Rigueur D, Lyons KM. TGFβ as a gatekeeper of BMP action in the developing growth plate. Bone. August 2020;137:115439.
2021	Kaur T, John AA, Sharma C, Vashisht NK, Singh D, Kapila R, Kapila S. miR300 intervenes Smad3/β-catenin/RunX2 crosstalk for therapy with an alternate function as indicative biomarker in osteoporosis. Bone. February 2021;143:115603.
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2022	Zhou P, Zheng T, Zhao B. Cytokine-mediated immunomodulation of osteoclastogenesis. Bone. November 2022;164:116540.
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2023	Mierzejewski B, Pulik Ł, Grabowska I, Sibilska A, Ciemerych MA, Łęgosz P, Brzoska E. Coding and noncoding RNA profile of human heterotopic ossifications: risk factors and biomarkers. Bone. November 2023;176:116883.
2023	Ye H, Cao L, Jackson-Weaver O, Zheng L, Gou Y. PRMT1-mediated arginine methylation promotes postnatal calvaria bone formation through BMP-Smad signaling. Bone. November 2023;176:116887.
2023	Hu X, Foster BL, Zhao B, Tseng HC, Wu Y-C, Ko C-C. Optineurin regulates osteoblast function in an age-dependent fashion in a mouse model of Paget's disease of bone. Bone. December 2023;177:116929.
2020	Kushioka J, Kaito T, Okada R, Ishiguro H, Bal Z, Kodama J, Chijimatsu R, Pye M, Narimatsu M, Wrana JL, Inoue Y, Ninomiya H, Yamamoto S, Saitou T, Yoshikawa H, Imamura T. A novel negative regulatory mechanism of Smurf2 in BMP/sSmad signaling in bone. Bone Res. 2020;8:41.
2020	Al-Rawi R, Al-Beshri A, Mikhail FM, McCormick K. Fragile bones secondary to SMURF1 gene duplication. Calcif Tiss Int. May 2020;106(5):567-573.
2020	Xu J, Liu J, Gan Y, Dai K, Zhao J, Huang M, Huang Y, Zhuang Y, Zhang X. High‐dose TGF‐Β1 impairs mesenchymal stem cell–mediated bone regeneration via Bmp2 inhibition. J Bone Miner Res. January 2020;35(1):167-180.
2020	Dole NS, Yee CS, Mazur CM, Acevedo C, Alliston T. TGFΒ regulation of perilacunar/canalicular remodeling is sexually dimorphic. J Bone Miner Res. August 2020;35(8):1549-1561.
2020	Lademann F, Weidner H, Tsourdi E, Kumar R, Rijntjes E, Köhrle J, Hofbauer LC, Rauner M. Disruption of BMP signaling prevents hyperthyroidism‐induced bone loss in male mice. J Bone Miner Res. October 2020;35(10):2058-2069.
2021	Stavnichuk M, Tauer JT, Nagy Z, Mazharian A, Welman M, Lordkipanidzé M, Senis YA, Komarova SV. Severity of megakaryocyte‐driven osteosclerosis in Mpig6b‐deficient mice is sex‐linked. J Bone Miner Res. April 2021;36(4):803-813.
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2023	Shi C, Sun B, Wu H, Zhang R, Wu L, Guo L, Li C, Xi Y, Yuan W, Zhang Y, Xu G. Dysfunction of caveolae-mediated endocytic TβRI degradation results in hypersensitivity of TGF-β/Smad signaling in osteogenesis imperfecta. J Bone Miner Res. January 2023;38(1):103-118.
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2023	Mercier-Guery A, Millet M, Merle B, Collet C, Bagouet F, Borel O, Sornay-Rendu E, Szulc P, Vignot E, Gensburger D, Fontanges E, Croset M, Chapurlat R. Dysregulation of microRNAs in adult osteogenesis imperfecta: the miROI study. J Bone Miner Res. November 2023;38(11):1665-1678.
2021	Al Hamed FSM. Role of Plasma Composition on Bone Healing and Implant Osseointegration [PhD thesis]. McGill University; March 2021.
2016	Sebastian A. High-Throughput Analysis of WNT Signaling Pathway in Osteoblasts [PhD thesis]. Merced, CA: Merced, University of California; 2016.
2018	Wang X. Investigating the Role of PDGF-BB/PDGFR-Β in Periosteum-Mediated Bone Regeneration [PhD thesis]. Storrs, CT: University of Connecticut; 2018.
2017	Nguyen J. TGFΒ Signaling in Load-Induced Bone Formation [PhD thesis]. San Francisco, University of California; 2017.
2020	Monteiro DA. Physical Cues Regulate the Localization and Activation of TGFβ Receptors to Control the Quantity and Quality of Signaling Pathway Activity [PhD thesis]. San Francisco, University of California; 2020.
2021	Rivera KO. Localized Neurotrophin Delivery Via Microparticles for Enhanced Bone Fracture Repair [PhD thesis]. San Francisco, University of California; 2021.
2022	Schurman CA. The Role of TGFβ Mediated Osteocytic Perilacunar/canalicular Remodeling in Age-Related Bone Fragility [PhD thesis]. San Francisco, University of California; 2022.
2023	Halloran DR. Investigating Aberrant Bone Morphogenetic Protein-2 Signaling in Aged C57bl/6 Mice That is Reflective of Osteoporotic Patients [PhD thesis]. University of Delaware; Spring 2023.
2022	St. Amant J. Interplay Between Integrin Alpha 1 Beta 1 and Transforming Growth Factor Beta Receptor II in the Development of Spontaneous Osteoarthritis in the Mouse Knee [Master's thesis]. University of Guelph; September 2022.
2020	Kegelman CD. Combinatorial Roles of Skeletal Cell YAP and TAZ in Bone Growth, Remodeling, and Repair [PhD thesis]. Philadelphia, PA: University of Pennsylvania; 2020.