Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Drug Targets
  4. Volume 26, Issue 5
  5. Article
Volume 26, Issue 5
  • ISSN: 1389-4501
  • E-ISSN: 1873-5592

Abstract

Diseases affecting bone encompass a spectrum of disorders, from prevalent conditions such as osteoporosis and Paget's disease, collectively impacting millions, to rare genetic disorders including Fibrodysplasia Ossificans Progressiva (FOP). While several classes of drugs, such as bisphosphonates, synthetic hormones, and antibodies, are utilized in the treatment of bone diseases, their efficacy is often curtailed by issues of tolerability and high incidence of adverse effects. Developing therapeutic agents for bone diseases is hampered by the fact that numerous pathways regulating bone metabolism also perform pivotal functions in other organ systems. Consequently, the selection of an appropriate target is a complicated process despite the significant demand for novel medications to address bone diseases. Research has shown the role of various cell signaling pathways, including Wnt, PTHR1, CASR, BMPRs, OSCAR, and TWIST1, in the regulation of osteogenesis, bone remodeling, and homeostasis. Disruptions in bone homeostasis can result in decreased bone density and the onset of osteoporosis. There remains a need for the development of drugs that can enhance bone remodeling with improved side effects profiles. The exploration of promising targets to stimulate bone formation has the potential to significantly advance the field of bone-related medical care, thereby improving the quality of life for millions. Additionally, a deeper understanding of anabolic and catabolic pathway mechanisms could enable future studies to explore synergistic effects between unrelated pathways. Herein, we explore potential drug targets that may be exploited therapeutically using small molecule agonists or antagonists to promote bone remodeling and discuss their advantages and limitations.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cdt/10.2174/0113894501359782241216082049
2025-01-08
2025-05-08

  • From This Site

    /content/journals/cdt/10.2174/0113894501359782241216082049
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Santa MariaC. ChengZ. LiA. WangJ. ShobackD. TuC.L. ChangW. Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism.Semin. Cell Dev. Biol.201649112310.1016/j.semcdb.2015.12.00426688334
     [Google Scholar]
  2. AlmalkiS.G. AgrawalD.K. Key transcription factors in the differentiation of mesenchymal stem cells.Differentiation2016921-2415110.1016/j.diff.2016.02.00527012163
     [Google Scholar]
  3. ChoiJ.U.A. KijasA.W. LaukoJ. RowanA.E. The mechanosensory role of osteocytes and implications for bone health and disease states.Front. Cell Dev. Biol.2022977014310.3389/fcell.2021.77014335265628
     [Google Scholar]
  4. NakashimaT. HayashiM. FukunagaT. KurataK. Oh-horaM. FengJ.Q. BonewaldL.F. KodamaT. WutzA. WagnerE.F. PenningerJ.M. TakayanagiH. Evidence for osteocyte regulation of bone homeostasis through RANKL expression.Nat. Med.201117101231123410.1038/nm.245221909105
     [Google Scholar]
  5. FuQ. Bustamante-GomezN.C. Reyes-PardoH. GubrijI. Escalona-VargasD. ThostensonJ.D. PalmieriM. GoellnerJ.J. NookaewI. BarnesC.L. StamboughJ.B. AmbroginiE. O’BrienC.A. Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation.JCI Insight2023818e16779010.1172/jci.insight.16779037581932
     [Google Scholar]
  6. BoyceB. YaoZ. XingL. Osteoclasts have multiple roles in bone in addition to bone resorption.Crit. Rev. Eukaryot. Gene Expr.200919317118010.1615/CritRevEukarGeneExpr.v19.i3.1019883363
     [Google Scholar]
  7. TresguerresF.G.F. TorresJ. López-QuilesJ. HernándezG. VegaJ.A. TresguerresI.F. The osteocyte: A multifunctional cell within the bone.Ann. Anat.202022715142210.1016/j.aanat.2019.15142231563568
     [Google Scholar]
  8. ZhangY. PolmanM. MohammadA.F. HermensI. ZhuangZ. WangH. van den BeuckenJ.J.J.P. Species-independent stimulation of osteogenic differentiation induced by osteoclasts.Biochem. Biophys. Res. Commun.202260614915510.1016/j.bbrc.2022.03.11535358839
     [Google Scholar]
  9. ChenX. WangZ. DuanN. ZhuG. SchwarzE.M. XieC. Osteoblast–osteoclast interactions.Connect. Tissue Res.20185929910710.1080/03008207.2017.129008528324674
     [Google Scholar]
  10. IkebuchiY. AokiS. HonmaM. HayashiM. SugamoriY. KhanM. KariyaY. KatoG. TabataY. PenningerJ.M. UdagawaN. AokiK. SuzukiH. Coupling of bone resorption and formation by RANKL reverse signalling.Nature2018561772219520010.1038/s41586‑018‑0482‑730185903
     [Google Scholar]
  11. EastellR. O’NeillT.W. HofbauerL.C. LangdahlB. ReidI.R. GoldD.T. CummingsS.R. Postmenopausal osteoporosis.Nat. Rev. Dis. Primers2016211606910.1038/nrdp.2016.6927681935
     [Google Scholar]
  12. IshtiaqS. FogelmanI. HampsonG. Treatment of post-menopausal osteoporosis: Beyond bisphosphonates.J. Endocrinol. Invest.2015381132910.1007/s40618‑014‑0152‑z25194424
     [Google Scholar]
  13. ChelohaR.W. GellmanS.H. VilardagaJ.P. GardellaT.J. PTH receptor-1 signalling—mechanistic insights and therapeutic prospects.Nat. Rev. Endocrinol.2015111271272410.1038/nrendo.2015.13926303600
     [Google Scholar]
  14. ChenT. WangY. HaoZ. HuY. LiJ. Parathyroid hormone and its related peptides in bone metabolism.Biochem. Pharmacol.202119211466910.1016/j.bcp.2021.11466934224692
     [Google Scholar]
  15. ParkD.R. KimJ. KimG.M. LeeH. KimM. HwangD. LeeH. KimH.S. KimW. ParkM.C. ShimH. LeeS.Y. Osteoclast-associated receptor blockade prevents articular cartilage destruction via chondrocyte apoptosis regulation.Nat. Commun.2020111434310.1038/s41467‑020‑18208‑y32859940
     [Google Scholar]
  16. SingerF.R. BoneH.G.III HoskingD.J. LylesK.W. MuradM.H. ReidI.R. SirisE.S. Endocrine Society Paget’s disease of bone: An endocrine society clinical practice guideline.J. Clin. Endocrinol. Metab.201499124408442210.1210/jc.2014‑291025406796
     [Google Scholar]
  17. KangH. ParkY.C. YangK.H. Paget’s disease: Skeletal manifestations and effect of bisphosphonates.J. Bone Metab.20172429710310.11005/jbm.2017.24.2.9728642853
     [Google Scholar]
  18. ChoiY.J. SohnY.B. ChungY.S. Updates on paget’s disease of bone.Endocrinol. Metab.202237573274310.3803/EnM.2022.157536327984
     [Google Scholar]
  19. RalstonS.H. Corral-GudinoL. CooperC. FrancisR.M. FraserW.D. GennariL. GuañabensN. JavaidM.K. LayfieldR. O’NeillT.W. RussellR.G.G. StoneM.D. SimpsonK. WilkinsonD. WillsR. ZillikensM.C. TuckS.P. Diagnosis and management of Paget’s disease of bone in adults: A clinical guideline.J. Bone Miner. Res.201934457960410.1002/jbmr.365730803025
     [Google Scholar]
  20. MuschitzC. FeichtingerX. HaschkaJ. KocijanR. Diagnosis and treatment of Paget’s disease of bone.Wien. Med. Wochenschr.20171671-2182410.1007/s10354‑016‑0502‑x27600563
     [Google Scholar]
  21. BlackD.M. DelmasP.D. EastellR. ReidI.R. BoonenS. CauleyJ.A. CosmanF. LakatosP. LeungP.C. ManZ. MautalenC. MesenbrinkP. HuH. CaminisJ. TongK. Rosario-JansenT. KrasnowJ. HueT.F. SellmeyerD. EriksenE.F. CummingsS.R. HORIZON Pivotal Fracture Trial Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.N. Engl. J. Med.2007356181809182210.1056/NEJMoa06731217476007
     [Google Scholar]
  22. DrakeM.T. ClarkeB.L. KhoslaS. Bisphosphonates: Mechanism of action and role in clinical practice.Mayo Clin. Proc.20088391032104510.4065/83.9.103218775204
     [Google Scholar]
  23. Mejias RiveraL. ShoreE.M. MourkiotiF. Cellular and molecular mechanisms of heterotopic ossification in fibrodysplasia ossificans progressiva.Biomedicines202412477910.3390/biomedicines1204077938672135
     [Google Scholar]
  24. WilleyJ.S. LloydS.A.J. NelsonG.A. BatemanT.A. Ionizing radiation and bone loss: Space exploration and clinical therapy applications.Clin. Rev. Bone Miner. Metab.201191546210.1007/s12018‑011‑9092‑822826690
     [Google Scholar]
  25. LiD. SunJ. ZhongT.P. Wnt signaling in heart development and regeneration.Curr. Cardiol. Rep.202224101425143810.1007/s11886‑022‑01756‑835925512
     [Google Scholar]
  26. LiuJ. XiaoQ. XiaoJ. NiuC. LiY. ZhangX. ZhouZ. ShuG. YinG. Wnt/β-catenin signalling: Function, biological mechanisms, and therapeutic opportunities.Signal Transduct. Target. Ther.202271310.1038/s41392‑021‑00762‑634980884
     [Google Scholar]
  27. HuL. ChenW. QianA. LiY.P. Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease.Bone Res.20241213910.1038/s41413‑024‑00342‑838987555
     [Google Scholar]
  28. MariniF. GiustiF. PalminiG. BrandiM.L. Role of Wnt signaling and sclerostin in bone and as therapeutic targets in skeletal disorders.Osteoporos. Int.202334221323810.1007/s00198‑022‑06523‑735982318
     [Google Scholar]
  29. Appelman-DijkstraN.M. PapapoulosS.E. Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway.Nat. Rev. Endocrinol.2018141060562310.1038/s41574‑018‑0087‑030181608
     [Google Scholar]
  30. WeivodaM.M. RuanM. PedersonL. HachfeldC. DaveyR.A. ZajacJ.D. WestendorfJ.J. KhoslaS. OurslerM.J. Osteoclast TGF-β receptor signaling induces wnt1 secretion and couples bone resorption to bone formation.J. Bone Miner. Res.2016311768510.1002/jbmr.258626108893
     [Google Scholar]
  31. GlassD.A.II BialekP. AhnJ.D. StarbuckM. PatelM.S. CleversH. TaketoM.M. LongF. McMahonA.P. LangR.A. KarsentyG. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation.Dev. Cell20058575176410.1016/j.devcel.2005.02.01715866165
     [Google Scholar]
  32. SongL. LiuM. OnoN. BringhurstF.R. KronenbergH.M. GuoJ. Loss of wnt/β-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes.J. Bone Miner. Res.201227112344235810.1002/jbmr.169422729939
     [Google Scholar]
  33. WanY. LuC. CaoJ. ZhouR. YaoY. YuJ. ZhangL. ZhaoH. LiH. ZhaoJ. ZhuX. HeL. LiuY. YaoZ. YangX. GuoX. Osteoblastic Wnts differentially regulate bone remodeling and the maintenance of bone marrow mesenchymal stem cells.Bone201355125826710.1016/j.bone.2012.12.05223334081
     [Google Scholar]
  34. LittleR.D. FolzC. ManningS.P. SwainP.M. ZhaoS-C. EustaceB. LappeM.M. SpitzerL. ZweierS. BraunschweigerK. BenchekrounY. HuX. AdairR. CheeL. FitzGeraldM.G. TuligC. CarusoA. TzellasN. BawaA. FranklinB. McGuireS. NoguesX. GongG. AllenK.M. AnisowiczA. MoralesA.J. LomedicoP.T. ReckerS.M. Van EerdeweghP. ReckerR.R. CarulliJ.P. Del MastroR.G. DupuisJ. OsborneM. JohnsonM.L. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.Am. J. Hum. Genet.2002701111910.1086/33845011741193
     [Google Scholar]
  35. MatsushitaY. NagataM. KozloffK.M. WelchJ.D. MizuhashiK. TokavanichN. HallettS.A. LinkD.C. NagasawaT. OnoW. OnoN. A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration.Nat. Commun.202011133210.1038/s41467‑019‑14029‑w31949165
     [Google Scholar]
  36. MaG. HeJ. YuY. XuY. YuX. MartinezJ. LonardD.M. XuJ. Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation.Int. J. Biol. Sci.201511561862810.7150/ijbs.1138025892968
     [Google Scholar]
  37. QuartoN. Senarath-YapaK. RendaA. LongakerM.T. TWIST1 silencing enhances in vitro and in vivo osteogenic differentiation of human adipose-derived stem cells by triggering activation of BMP-ERK/FGF signaling and TAZ upregulation.Stem Cells201533383384710.1002/stem.190725446627
     [Google Scholar]
  38. MinisolaS. Romosozumab: From basic to clinical aspects.Expert Opin. Biol. Ther.20141491225122810.1517/14712598.2014.92081524835636
     [Google Scholar]
  39. EriksenE.F. ChapurlatR. BoyceR.W. ShiY. BrownJ.P. HorlaitS. BetahD. LibanatiC. ChavassieuxP. Modeling-based bone formation after 2 months of romosozumab treatment: Results from the FRAME clinical trial.J. Bone Miner. Res.2020371364010.1002/jbmr.445734633116
     [Google Scholar]
  40. HongN. ShinS. KimH. ChoS.J. ParkJ.A. RheeY. Romosozumab following denosumab improves lumbar spine bone mineral density and trabecular bone score greater than denosumab continuation in postmenopausal women.J. Bone Miner. Res.2024zjae17910.1093/jbmr/zjae17939485918
     [Google Scholar]
  41. StokarJ. SzalatA. Cardiovascular safety of romosozumab vs PTH analogues for osteoporosis treatment: A propensity-score-matched cohort study.J. Clin. Endocrinol. Metab.2024dgae17310.1210/clinem/dgae17338482603
     [Google Scholar]
  42. EriksenE.F. BoyceR.W. ShiY. BrownJ.P. BetahD. LibanatiC. OatesM. ChapurlatR. ChavassieuxP. Reconstruction of remodeling units reveals positive effects after 2 and 12 months of romosozumab treatment.J. Bone Miner. Res.202439672973610.1093/jbmr/zjae05538640512
     [Google Scholar]
  43. ChengS.H. ChuW. ChouW.H. ChuW.C. KangY.N. Cardiovascular safety of romosozumab compared to commonly used anti-osteoporosis medications in postmenopausal osteoporosis: A systematic review and network meta-analysis of randomized controlled trials.Drug Saf.202548172310.1007/s40264‑024‑01475‑939227560
     [Google Scholar]
  44. MarkhamA. Romosozumab: First global approval.Drugs201979447147610.1007/s40265‑019‑01072‑630805895
     [Google Scholar]
  45. ZhongY. LiX. ZhuD. ZhaoN. YaoH. LinK. Characteristics of parathyroid hormone-1 receptor agonists and antagonists.Future Med. Chem.201911881783110.4155/fmc‑2018‑050830998079
     [Google Scholar]
  46. LiuH. LiuL. RosenC.J. PTH and the regulation of mesenchymal cells within the bone marrow niche.Cells202413540610.3390/cells1305040638474370
     [Google Scholar]
  47. YavropoulouM.P. MichopoulosA. YovosJ.G. PTH and PTHR1 in osteocytes. New insights into old partners.Hormones201716215016010.14310/horm.2002.173028742503
     [Google Scholar]
  48. WuM. DengL. ZhuG. LiY.P.G. G Protein and its signaling pathway in bone development and disease.Front. Biosci.201015195798510.2741/365620515736
     [Google Scholar]
  49. YangY. WangB. PTH1R-CaSR cross talk: New treatment options for breast cancer osteolytic bone metastases.Int. J. Endocrinol.201820181810.1155/2018/712097930151009
     [Google Scholar]
  50. QinL. RaggattL.J. PartridgeN.C. Parathyroid hormone: A double-edged sword for bone metabolism.Trends Endocrinol. Metab.2004152606510.1016/j.tem.2004.01.00615036251
     [Google Scholar]
  51. Rendina-RuedyE. RosenC.J. Parathyroid hormone (PTH) regulation of metabolic homeostasis: An old dog teaches us new tricks.Mol. Metab.20226010148010.1016/j.molmet.2022.10148035338013
     [Google Scholar]
  52. HiremathM. DannP. FischerJ. ButterworthD. Boras-GranicK. HensJ. Van HoutenJ. ShiW. WysolmerskiJ. Parathyroid hormone-related protein activates Wnt signaling to specify the embryonic mammary mesenchyme.Development2012139224239424910.1242/dev.08067123034629
     [Google Scholar]
  53. MartinT.J. PTH1R actions on bone using the cAMP/protein kinase a pathway.Front. Endocrinol.20221283322110.3389/fendo.2021.83322135126319
     [Google Scholar]
  54. SimI.W. BorromeoG.L. TsaoC. HardimanR. HofmanM.S. Papatziamos HjelleC. SiddiqueM. CookG.J.R. SeymourJ.F. EbelingP.R. Teriparatide promotes bone healing in medication-related osteonecrosis of the jaw: A placebo- controlled, randomized trial.J. Clin. Oncol.202038262971298010.1200/JCO.19.0219232614699
     [Google Scholar]
  55. TangY. XiaH. KangL. SunQ. SuZ. HaoC. XueY. Effects of intermittent parathyroid hormone 1–34 administration on circulating mesenchymal stem cells in postmenopausal osteoporotic women.Med. Sci. Monit.20192525926810.12659/MSM.91375230620727
     [Google Scholar]
  56. NeerR.M. ArnaudC.D. ZanchettaJ.R. PrinceR. GaichG.A. ReginsterJ.Y. HodsmanA.B. EriksenE.F. Ish-ShalomS. GenantH.K. WangO. MellströmD. OefjordE.S. Marcinowska-SuchowierskaE. SalmiJ. MulderH. HalseJ. SawickiA.Z. MitlakB.H. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.N. Engl. J. Med.2001344191434144110.1056/NEJM20010510344190411346808
     [Google Scholar]
  57. YamaguchiT. The calcium-sensing receptor in bone.J. Bone Miner. Metab.200826430131110.1007/s00774‑008‑0843‑718600395
     [Google Scholar]
  58. ZhangL.X. ZhangB. LiuX.Y. WangZ.M. QiP. ZhangT.Y. ZhangQ. Advances in the treatment of secondary and tertiary hyperparathyroidism.Front. Endocrinol.202213105982810.3389/fendo.2022.105982836561571
     [Google Scholar]
  59. SaremM. HeizmannM. BarberoA. MartinI. ShastriV.P. Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R.Proc. Natl. Acad. Sci. USA201811527E6135E614410.1073/pnas.180515911529915064
     [Google Scholar]
  60. FukagawaM. ShimazakiR. AkizawaT. Evocalcet study group Head-to-head comparison of the new calcimimetic agent evocalcet with cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism.Kidney Int.201894481882510.1016/j.kint.2018.05.01330049473
     [Google Scholar]
  61. FangD. ChenH. Association between serum calcium level and in-hospital mortality in patients with acute myocardial infarction: A retrospective cohort study.Sci. Rep.20221211995410.1038/s41598‑022‑24566‑y36402887
     [Google Scholar]
  62. DongB. EndoI. OhnishiY. MitsuiY. KurahashiK. KanaiM. HiasaM. TeramachiJ. TenshinH. FukumotoS. AbeM. MatsumotoT. Persistent activation of calcium-sensing receptor suppresses bone turnover, increases microcracks, and decreases bone strength.JBMR Plus201937e1018210.1002/jbm4.1018231372589
     [Google Scholar]
  63. CosmanF. CrittendenD.B. AdachiJ.D. BinkleyN. CzerwinskiE. FerrariS. HofbauerL.C. LauE. LewieckiE.M. MiyauchiA. ZerbiniC.A.F. MilmontC.E. ChenL. MaddoxJ. MeisnerP.D. LibanatiC. GrauerA. Romosozumab treatment in postmenopausal women with osteoporosis.N. Engl. J. Med.2016375161532154310.1056/NEJMoa160794827641143
     [Google Scholar]
  64. OgataM. UshimaruS. FujishimaR. SumiH. ShiizakiK. TominagaN. Romosozumab improves low bone mineral density in a postmenopausal woman undergoing chronic hemodialysis and treated with a calcium-sensing receptor agonist.Bone Rep.20221710163910.1016/j.bonr.2022.101639
     [Google Scholar]
  65. ValerJ.A. Sánchez-de-DiegoC. Pimenta-LopesC. RosaJ.L. VenturaF. ACVR1 function in health and disease.Cells2019811136610.3390/cells811136631683698
     [Google Scholar]
  66. OmiM. KaartinenV. MishinaY. Activin A receptor type 1–mediated BMP signaling regulates RANKL-induced osteoclastogenesis via canonical SMAD-signaling pathway.J. Biol. Chem.201929447178181783610.1074/jbc.RA119.00952131619522
     [Google Scholar]
  67. YadinD. KnausP. MuellerT.D. Structural insights into BMP receptors: Specificity, activation and inhibition.Cytokine Growth Factor Rev.201627133410.1016/j.cytogfr.2015.11.00526690041
     [Google Scholar]
  68. Sanchez-DuffhuesG. WilliamsE. GoumansM.J. HeldinC.H. ten DijkeP. Bone morphogenetic protein receptors: Structure, function and targeting by selective small molecule kinase inhibitors.Bone202013811547210.1016/j.bone.2020.11547232522605
     [Google Scholar]
  69. ChenD. ZhaoM. MundyG.R. Bone morphogenetic proteins.Growth Factors200422423324110.1080/0897719041233127989015621726
     [Google Scholar]
  70. ChenG. DengC. LiY.P. TGF-β and BMP signaling in osteoblast differentiation and bone formation.Int. J. Biol. Sci.20128227228810.7150/ijbs.292922298955
     [Google Scholar]
  71. ZhangX. LiuQ. ZhaoH. HuY. LiuC. YanG. LiD. MishinaY. ShiC. SunH. ACVR1 is essential for periodontium development and promotes alveolar bone formation.Arch. Oral Biol.20189510811710.1016/j.archoralbio.2018.07.01930098439
     [Google Scholar]
  72. HuY. HaoX. LiuC. RenC. WangS. YanG. MengY. MishinaY. ShiC. SunH. Acvr1 deletion in osteoblasts impaired mandibular bone mass through compromised osteoblast differentiation and enhanced sRANKL-induced osteoclastogenesis.J. Cell. Physiol.202123664580459110.1002/jcp.3018333251612
     [Google Scholar]
  73. LuoJ. TangM. HuangJ. HeB.C. GaoJ.L. ChenL. ZuoG.W. ZhangW. LuoQ. ShiQ. ZhangB.Q. BiY. LuoX. JiangW. SuY. ShenJ. KimS.H. HuangE. GaoY. ZhouJ.Z. YangK. LuuH.H. PanX. HaydonR.C. DengZ.L. HeT.C. TGFbeta/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells.J. Biol. Chem.201028538295882959810.1074/jbc.M110.13051820628059
     [Google Scholar]
  74. KaplanF.S. SeemannP. HauptJ. XuM. LounevV.Y. MullinsM. ShoreE.M. Investigations of activated ACVR1/ALK2, a bone morphogenetic protein type I receptor, that causes fibrodysplasia ossificans progressiva.Methods Enzymol.201048435737310.1016/B978‑0‑12‑381298‑8.00018‑621036241
     [Google Scholar]
  75. YamamotoM. StoesselS.J. YamamotoS. GoldhamerD.J. Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification.J. Bone Miner. Res.202037112077209310.1002/jbmr.461735637634
     [Google Scholar]
  76. AgarwalS. LoderS.J. BrownleyC. EbodaO. PetersonJ.R. HayanoS. WuB. ZhaoB. KaartinenV. WongV.C. MishinaY. LeviB. BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints.Dev. Biol.2015400220220910.1016/j.ydbio.2015.02.01125722188
     [Google Scholar]
  77. PacificiM. ShoreE.M. Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders.Cytokine Growth Factor Rev.2016279310410.1016/j.cytogfr.2015.12.00726776312
     [Google Scholar]
  78. HatsellS.J. IdoneV. WolkenD.M.A. HuangL. KimH.J. WangL. WenX. NannuruK.C. JimenezJ. XieL. DasN. MakhoulG. ChernomorskyR. D’AmbrosioD. CorpinaR.A. SchoenherrC.J. FeeleyK. YuP.B. YancopoulosG.D. MurphyA.J. EconomidesA.N. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.Sci. Transl. Med.20157303303ra13710.1126/scitranslmed.aac435826333933
     [Google Scholar]
  79. RamachandranA. MehićM. WasimL. MalinovaD. GoriI. BlaszczykB.K. CarvalhoD.M. ShoreE.M. JonesC. HyvönenM. TolarP. HillC.S. Pathogenic ACVR1 R206H activation by Activin A-induced receptor clustering and autophosphorylation.EMBO J.20214014e10631710.15252/embj.202010631734003511
     [Google Scholar]
  80. HinoK. HorigomeK. NishioM. KomuraS. NagataS. ZhaoC. JinY. KawakamiK. YamadaY. OhtaA. ToguchidaJ. IkeyaM. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva.J. Clin. Invest.201712793339335210.1172/JCI9352128758906
     [Google Scholar]
  81. FukudaT. KohdaM. KanomataK. NojimaJ. NakamuraA. KamizonoJ. NoguchiY. IwakiriK. KondoT. KuroseJ. EndoK. AwakuraT. FukushiJ. NakashimaY. ChiyonobuT. KawaraA. NishidaY. WadaI. AkitaM. KomoriT. NakayamaK. NanbaA. MarukiY. YodaT. TomodaH. YuP.B. ShoreE.M. KaplanF.S. MiyazonoK. MatsuokaM. IkebuchiK. OhtakeA. OdaH. JimiE. OwanI. OkazakiY. KatagiriT. Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva.J. Biol. Chem.2009284117149715610.1074/jbc.M80168120018684712
     [Google Scholar]
  82. WangY. NguyenJ.H. de RuiterR.D. MendellJ. SrinivasanD. DavisJ.D. EekhoffE.M.W. Garetosmab in Fibrodysplasia ossificans progressiva: Clinical pharmacology results from the phase 2 LUMINA-1 trial.J. Clin. Pharmacol.202464226427410.1002/jcph.234437694449
     [Google Scholar]
  83. KamiyaN. KaartinenV.M. MishinaY. Loss-of-function of ACVR1 in osteoblasts increases bone mass and activates canonical Wnt signaling through suppression of Wnt inhibitors SOST and DKK1.Biochem. Biophys. Res. Commun.2011414232633010.1016/j.bbrc.2011.09.06021945937
     [Google Scholar]
  84. WangY. SunJ.C. WangH.B. XuX.M. KongQ.J. WangY.J. ZhengB. ShiG.D. ShiJ.G. ACVR1-knockout promotes osteogenic differentiation by activating the Wnt signaling pathway in mice.J. Cell. Biochem.201912058185819410.1002/jcb.2810030556170
     [Google Scholar]
  85. PetersonJ.R. EbodaO. AgarwalS. RanganathanK. BuchmanS.R. LeeM. WangS.C. MishinaY. LeviB. Targeting of ALK2, a receptor for bone morphogenetic proteins, using the Cre/lox system to enhance osseous regeneration by adipose-derived stem cells.Stem Cells Transl. Med.20143111375138010.5966/sctm.2014‑008225232183
     [Google Scholar]
  86. ShiC. MandairG.S. ZhangH. VanrenterghemG.G. RidellaR. TakahashiA. ZhangY. KohnD.H. MorrisM.D. MishinaY. SunH. Bone morphogenetic protein signaling through ACVR1 and BMPR1A negatively regulates bone mass along with alterations in bone composition.J. Struct. Biol.2018201323724610.1016/j.jsb.2017.11.01029175363
     [Google Scholar]
  87. TobeihaM. MoghadasianM.H. AminN. JafarnejadS. RANKL/RANK/OPG pathway: A mechanism involved in exercise-induced bone remodeling.BioMed Res. Int.2020202011110.1155/2020/691031232149122
     [Google Scholar]
  88. BarrowA.D. RaynalN. AndersenT.L. SlatterD.A. BihanD. PughN. CellaM. KimT. RhoJ. Negishi-KogaT. DelaisseJ.M. TakayanagiH. LorenzoJ. ColonnaM. FarndaleR.W. ChoiY. TrowsdaleJ. OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice.J. Clin. Invest.201112193505351610.1172/JCI4591321841309
     [Google Scholar]
  89. VitaleM. LigorioC. RichardsonS.M. HoylandJ.A. BellaJ. Collagen-like osteoclast-associated receptor (OSCAR)-binding motifs show a co-stimulatory effect on osteoclastogenesis in a peptide hydrogel system.Int. J. Mol. Sci.202325144510.3390/ijms2501044538203618
     [Google Scholar]
  90. NedevaI.R. VitaleM. ElsonA. HoylandJ.A. BellaJ. Role of OSCAR signaling in osteoclastogenesis and bone disease.Front. Cell Dev. Biol.2021964116210.3389/fcell.2021.64116233912557
     [Google Scholar]
  91. DaponteV. HenkeK. DrissiH. Current perspectives on the multiple roles of osteoclasts: Mechanisms of osteoclast–osteoblast communication and potential clinical implications.eLife202413e9508310.7554/eLife.9508338591777
     [Google Scholar]
  92. HaywoodJ. QiJ. ChenC.C. LuG. LiuY. YanJ. ShiY. GaoG.F. Structural basis of collagen recognition by human osteoclast-associated receptor and design of osteoclastogenesis inhibitors.Proc. Natl. Acad. Sci. USA201611341038104310.1073/pnas.152257211326744311
     [Google Scholar]
  93. KimG.M. ParkD.R. NguyenT.T.H. KimJ. KimJ. SohnM.H. LeeW.K. LeeS.Y. ShimH. Development of anti-OSCAR antibodies for the treatment of osteoarthritis.Biomedicines20231110284410.3390/biomedicines1110284437893216
     [Google Scholar]
  94. KimG.M. ParkH. LeeS.Y. Roles of osteoclast-associated receptor in rheumatoid arthritis and osteoarthritis.Joint Bone Spine202289510540010.1016/j.jbspin.2022.10540035504517
     [Google Scholar]
  95. KimJ. RyuG. SeoJ. GoM. KimG. YiS. KimS. LeeH. LeeJ.Y. KimH.S. ParkM.C. ShinD.H. ShimH. KimW. LeeS.Y. 5-aminosalicylic acid suppresses osteoarthritis through the OSCAR-PPARγ axis.Nat. Commun.2024151102410.1038/s41467‑024‑45174‑638310093
     [Google Scholar]
  96. GoettschC. RaunerM. SinningenK. HelasS. Al-FakhriN. NemethK. HamannC. KoppraschS. AikawaE. BornsteinS.R. SchoppetM. HofbauerL.C. The osteoclast-associated receptor (OSCAR) is a novel receptor regulated by oxidized low-density lipoprotein in human endothelial cells.Endocrinology2011152124915492610.1210/en.2011‑128222009730
     [Google Scholar]
  97. MerckE. GaillardC. ScuillerM. ScapiniP. CassatellaM.A. TrinchieriG. BatesE.E.M. Ligation of the FcR gamma chain-associated human osteoclast-associated receptor enhances the proinflammatory responses of human monocytes and neutrophils.J. Immunol.200617653149315610.4049/jimmunol.176.5.314916493074
     [Google Scholar]
  98. BialekP. KernB. YangX. SchrockM. SosicD. HongN. WuH. YuK. OrnitzD.M. OlsonE.N. JusticeM.J. KarsentyG. A twist code determines the onset of osteoblast differentiation.Dev. Cell20046342343510.1016/S1534‑5807(04)00058‑915030764
     [Google Scholar]
  99. QinQ. XuY. HeT. QinC. XuJ. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms.Cell Res.20122219010610.1038/cr.2011.14421876555
     [Google Scholar]
  100. ThisseB. MessalM.E. Perrin-SchmittF. The twist gene: Isolation of a Drosophila zygotle gene necessary for the establishment of dorsoventral pattern.Nucleic Acids Res.19871583439345310.1093/nar/15.8.34393106932
     [Google Scholar]
  101. HagaC.L. BookerC.N. CarvalhoA. BoregowdaS.V. PhinneyD.G. Transcriptional targets of TWIST1 in human mesenchymal stem/stromal cells mechanistically link stem/progenitor and paracrine functions.Stem Cells202341121185120010.1093/stmcls/sxad07037665974
     [Google Scholar]
  102. LeeR.H. BoregowdaS.V. Shigemoto-KurodaT. BaeE. HagaC.L. AbberyC.A. BaylessK.J. HaskellA. GregoryC.A. OrtizL.A. PhinneyD.G. TWIST1 and TSG6 are coordinately regulated and function as potency biomarkers in human MSCs.Sci. Adv.2023945eadi238710.1126/sciadv.adi238737948519
     [Google Scholar]
  103. ChangA.T. LiuY. AyyanathanK. BennerC. JiangY. ProkopJ.W. PazH. WangD. LiH.R. FuX.D. RauscherF.J.III YangJ. An evolutionarily conserved DNA architecture determines target specificity of the TWIST family bHLH transcription factors.Genes Dev.201529660361610.1101/gad.242842.11425762439
     [Google Scholar]
  104. ZhangXW ZhangBY WangSW GongDJ HanL XuZY LiuXH Twist-related protein 1 negatively regulated osteoblastic transdifferentiation of human aortic valve interstitial cells by directly inhibiting runt-related transcription factor 2.J. Thorac. Cardiovasc. Surg.20141481700170810.1016/j.jtcvs.2014.02.084
     [Google Scholar]
  105. BookerC.N. HagaC.L. BoregowdaS.V. StrivelliJ. PhinneyD.G. Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts.NPJ Microgravity2021714910.1038/s41526‑021‑00178‑034836964
     [Google Scholar]
  106. BoregowdaS.V. KrishnappaV. HagaC.L. OrtizL.A. PhinneyD.G. A clinical indications prediction scale based on TWIST1 for human mesenchymal stem cells.EBioMedicine20164627310.1016/j.ebiom.2015.12.02026981553
     [Google Scholar]
  107. YangD.C. YangM.H. TsaiC.C. HuangT.F. ChenY.H. HungS.C. Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST.PLoS One201169e2396510.1371/journal.pone.002396521931630
     [Google Scholar]
  108. HayashiM. NimuraK. KashiwagiK. HaradaT. TakaokaK. KatoH. TamaiK. KanedaY. Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling.J. Cell Sci.200712081350135710.1242/jcs.00006717374642
     [Google Scholar]
  109. ShibataY. TsukazakiT. HirataK. XinC. YamaguchiA. Role of a new member of IGFBP superfamily, IGFBP-rP10, in proliferation and differentiation of osteoblastic cells.Biochem. Biophys. Res. Commun.200432541194120010.1016/j.bbrc.2004.10.15715555553
     [Google Scholar]
  110. PatelK. GadewarM. TripathiR. PrasadS.K. PatelD.K. A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid “Harmine”.Asian Pac. J. Trop. Biomed.20122866066410.1016/S2221‑1691(12)60116‑623569990
     [Google Scholar]
  111. YochumZ.A. CadesJ. MazzacuratiL. NeumannN.M. KhetarpalS.K. ChatterjeeS. WangH. AttarM.A. HuangE.H.B. ChatleyS.N. NugentK. SomasundaramA. EnghJ.A. EwaldA.J. ChoY.J. RudinC.M. TranP.T. BurnsT.F. A first-in-class TWIST1 inhibitor with activity in oncogene-driven lung cancer.Mol. Cancer Res.201715121764177610.1158/1541‑7786.MCR‑17‑029828851812
     [Google Scholar]
  112. NafieE. LolargaJ. LamB. GuoJ. AbdollahzadehE. RodriguezS. GlackinC. LiuJ. Harmine inhibits breast cancer cell migration and invasion by inducing the degradation of Twist1.PLoS One2021162e024765210.1371/journal.pone.024765233626096
     [Google Scholar]
  113. EgusaH. DoiM. SaekiM. FukuyasuS. AkashiY. YokotaY. YataniH. KamisakiY. The small molecule harmine regulates NFATc1 and Id2 expression in osteoclast progenitor cells.Bone201149226427410.1016/j.bone.2011.04.00321504804
     [Google Scholar]
  114. HuangJ. YinH. RaoS.S. XieP.L. CaoX. RaoT. LiuS.Y. WangZ.X. CaoJ. HuY. ZhangY. LuoJ. TanY.J. LiuZ.Z. WuB. HuX.K. ChenT.H. ChenC.Y. XieH. Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice.Theranostics2018892435244610.7150/thno.2214429721090
     [Google Scholar]
  115. YonezawaT. HasegawaS. AsaiM. NinomiyaT. SasakiT. ChaB.Y. TeruyaT. OzawaH. YagasakiK. NagaiK. WooJ.T. Harmine, a β-carboline alkaloid, inhibits osteoclast differentiation and bone resorption in vitro and in vivo .Eur. J. Pharmacol.20116502-351151810.1016/j.ejphar.2010.10.04821047508
     [Google Scholar]
  116. YonezawaT. LeeJ.W. HibinoA. AsaiM. HojoH. ChaB.Y. TeruyaT. NagaiK. ChungU.I. YagasakiK. WooJ.T. Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling.Biochem. Biophys. Res. Commun.2011409226026510.1016/j.bbrc.2011.05.00121570953
     [Google Scholar]
  117. FujiwaraN. LeeJ.W. Kumakami-SakanoM. OtsuK. WooJ.T. IsekiS. OtaM.S. Harmine promotes molar root development via SMAD1/5/8 phosphorylation.Biochem. Biophys. Res. Commun.2018497392492910.1016/j.bbrc.2017.12.06229253570
     [Google Scholar]
  118. XuY. QinW. GuoD. LiuJ. ZhangM. JinZ. LncRNA-TWIST1 promoted osteogenic differentiation both in PPDLSCs and in HPDLSCs by inhibiting TWIST1 expression.BioMed Res. Int.2019201911210.1155/2019/873595231341908
     [Google Scholar]
  119. HagaC.L. PhinneyD.G. MicroRNAs in the imprinted DLK1-DIO3 region repress the epithelial-to-mesenchymal transition by targeting the TWIST1 protein signaling network.J. Biol. Chem.201228751426954270710.1074/jbc.M112.38776123105110
     [Google Scholar]
  120. ZhangM. MengM. LiuY. QiJ. ZhaoZ. QiaoY. HuY. LuW. ZhouZ. XuP. ZhouQ. Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins.Breast Cancer Res.202123111610.1186/s13058‑021‑01488‑734922602
     [Google Scholar]
  121. CuiJ. LiX. WangS. SuY. ChenX. CaoL. ZhiX. QiuZ. WangY. JiangH. HuangB. JiF. SuJ. Triptolide prevents bone loss via suppressing osteoclastogenesis through inhibiting PI3K-AKT-NFATc1 pathway.J. Cell. Mol. Med.202024116149616110.1111/jcmm.1522932347017
     [Google Scholar]
  122. LuoD. RenH. ZhangH. ZhangP. HuangZ. XianH. LianK. LinD. The protective effects of triptolide on age-related bone loss in old male rats.Biomed. Pharmacother.20189828028510.1016/j.biopha.2017.12.07229274584
     [Google Scholar]
  123. ZulloA.R. LeeY. LaryC. DaielloL.A. KielD.P. BerryS.D. Comparative effectiveness of denosumab, teriparatide, and zoledronic acid among frail older adults: A retrospective cohort study.Osteoporos. Int.202132356557310.1007/s00198‑020‑05732‑233411003
     [Google Scholar]
  124. DharmapatniA.A.S.S.K. AlgateK. ColemanR. LorimerM. CantleyM.D. SmithM.D. WechalekarM.D. CrottiT.N. Osteoclast-associated receptor (OSCAR) distribution in the synovial tissues of patients with active RA and TNF-α and RANKL regulation of expression by osteoclasts in vitro .Inflammation20174051566157510.1007/s10753‑017‑0597‑228555364
     [Google Scholar]
/content/journals/cdt/10.2174/0113894501359782241216082049
Loading
Signaling Dynamics in Osteogenesis: Unraveling Therapeutic Targets for Bone Generation
Curr Drug Targets 26, 350 (2025); https://doi.org/10.2174/0113894501359782241216082049
/content/journals/cdt/10.2174/0113894501359782241216082049
/content/journals/cdt/10.2174/0113894501359782241216082049
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): ACVR1; bone homeostasis; bone remodeling; CASR; OSCAR; osteoblast; osteoclast; Osteogenesis; PTHR1; TWIST1

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test