Derleme
BibTex RIS Kaynak Göster

The Interrelationship Between Sclerostin and the Wnt Signaling Pathway

Yıl 2024, Cilt: 33 Sayı: 3, 186 - 197, 30.09.2024

Öz

Sclerostin is a glycoprotein that is crucial in bone metabolism and skeletal disorders. It is produced from the SOST gene, which is highly conserved among vertebrates. Osteocytes, bone cells that produce sclerostin, use this protein to antagonize osteoblasts’ canonical Wnt signaling pathway. This pathway is essential for bone formation as it promotes osteoblast proliferation, differentiation, and survival. However, when sclerostin inhibits this pathway, it reduces the +production of new bone tissue. Studies on animals have shown that mechanical loading can decrease sclerostin synthesis in osteocytes by reducing SOST gene expression. This means that when bones are subjected to mechanical stress, such as through exercise or weightlifting, the expression of the SOST gene decreases, leading to a reduction in sclerostin production. This reduction, in turn, increases Wnt signaling and bone formation. Conversely, when mechanical loading is eliminated, such as during prolonged periods of inactivity, sclerostin synthesis increases, leading to a decrease in bone formation. Sclerostin's inhibition of bone formation has been linked to several diseases with high bone mass. For example, sclerostin deficiency leads to sclerosteosis, a rare genetic disorder characterized by increased bone density and thickness. Similarly, another rare genetic disorder known as van Buchem disease is caused by a mutation in the SOST gene, which reduces sclerostin production and increases bone density. This review discusses the basics of Wnt signaling and its role in bone metabolism and skeletal disorders. It also evaluates the clinical significance and future implications of Wnt signaling in osteoporosis and osteoarthritis, two common conditions that affect bone health. Understanding the complex mechanisms of sclerostin and Wnt signaling is crucial for developing new treatments for bone-related diseases and improving bone health.

Kaynakça

  • 1. Cavalier E, Eastell R, Jørgensen N.R, et al. A Multicenter Study to Evaluate Harmonization of Assays for C-Terminal Telopeptides of Type I Collagen (ß-CTX): A Report from the IFCC-IOF Committee for Bone Metabolism (C-BM). Calcif Tissue Int 2021;08:785–797. https://doi.org/10.1007/s00223-021-00816-5
  • 2. Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin. Genet. 2003;63:192–197. https://doi.org/10.1034/j.1399-0004.2003.00036.x.
  • 3. Van Buchem F, Hadders H, Hansen J, Woldring M. Hyperostosis corticalis generalisata: Report of seven cases. Am. J. Med. 1962;33:387–397. https://doi.org/10.1016/0002-9343(62)90235-8.
  • 4. Lewiecki EM. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis. 2014;6(2):48–57. https://doi.org/10.1177/1759720x13510479
  • 5. Semenov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. 2005;280(29):26770–5. https://doi.org/10.1074/jbc.M504308200.
  • 6. Evenity MG HCP English—Amgen. Available online: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/evenity/evenity_mg_hcp_english.ashx. (accessed on 28 November 2021).
  • 7. European Medicines Agency. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/evenity (accessed on 28 November 2021).
  • 8. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 2001;10:537–544. https://doi.org/10.1093/hmg/10.5.537.
  • 9. Van Hul W, Balemans W, Van Hul E, Dikkers FG, Obee H, Stokroos RJ, Hildering P, Vanhoenacker F, Van Camp G, Willems PJ: Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am J Hum Genet 1998; 62: 391–399.
  • 10. Winkler DG, Yu C, Geoghegan JC, Ojala EW, Skonier JE, Shpektor D, et al. Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex. J Biol Chem 2004;279:36293–8. Httos://doi.org/10.1074/jbc.M400521200
  • 11. Veverka V, Henry A.J, Slocombe P.M, Ventom A, Mulloy B, Muskett F.W, Muzylak M, Greenslade K, Moore A, Zhang L, et al. Characterization of the structural features and interactions of sclerostin. J. Biol. Chem. 2009;284:10890–10900. https://doi.org/10.1074/jbc.M807994200
  • 12. Weivoda MM, Youssef SJ, Jo Oursler M. Sclerostin expression and functions beyond the osteocyte. J Bone 2017;96:45–50. https://doi.org/10.1016/j.bone.2016.11.024 30.
  • 13. Pietrzyk B, Smertka M, Chudek J. Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders. Adv Clin Exp Med 2017;26(8):1283–91. https://doi.org/ 10.17219/acem/68739.
  • 14. Sharma-Ghimire P, Chen Z, Sherk V, Bemben D. Sclerostin and parathyroid hormone responses to acute whole-body vibration and resistance exercise in young women. J Bone Miner Metab 2019;37:358–67. https://doi.org/ 10.1007/s00774-018-0933-0 35.
  • 15. Moester MJC, Papapoulos SE, Lowik CWGM, van Bezooijen RL. Sclerostin: current knowledge and future perspectives. Calcif Tissue Int 2010;87:99–107. https://doi.org/ 10.1007/s00223-010-9372-1
  • 16. Bonnet N, Garnero P, Ferrari S. Periostin action in bone. Mol Cell Endocrinol 2016;432:75–82. doi: 10.1016/j.mce.2015.12.014.
  • 17. Bonnet N, Standley KN, Bianchi EN, Stadelmann V, Foti M, Conway SJ, et al. The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity. J Biol Chem 2009;284(51):35939–50. doi: 10.1074/jbc.M109.060335.
  • 18. Maupin K.A, Droscha C.J. & Williams B.O. A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice. Bone Res. 2013;29;1(1):27-71. https://doi.org/10.4248/BR201301004.
  • 19. Sepici Dinçel A, Jorgensen N.S. New Emerging Biomarkers for Bone Disease: Sclerostin and Dickkopf-1 (DKK1).Calcified Tissue Inteernatiol. 2023;112 (2): 243-257. http://doi.org/10.1007/s00223-022-01020-9
  • 20. Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN, Komm BS, et al. Canonical Wnt signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem.2005;280(39):33132–40. https://doi.org/10.1074/jbc.m500608200.
  • 21. Zhang F, Zhao J, Liu X, Linhardt R.J. Interactions between sclerostin and glycosaminoglycans. Glycoconj. J. 2020; 37(1):119-128. https://doi.org/10.1007/s10719-019-09900-3.
  • 22. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of sost/ sclerostin. J Biol Chem 2008;283:5866–75. doi: 10.1074/jbc.M705092200
  • 23. Sharifi M, Ereifej L, Lewiecki EM. Sclerostin and skeletal health. Rev Endocr Metab Disord 2015;16:149–56. https://doi.org/ 10.1007/s11154-015-9311-6.
  • 24. Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375(16):1532–43. https://doi.org/10.1056/NEJMoa1607948.
  • 25. Brandenburg VM, D’Haese P, Deck A, Mekahli D, Meijers B, Neven E, et al. From skeletal to cardiovascular disease in 12 steps–the evolution of sclerostin as a major player in CKD-MBD. Pediatr Nephrol 2016;31:195–206. https:/doi.org/ 10.1007/ s00467-015-3069-7.
  • 26. Liu Y.Y, Wang S.Y, Li Y.N, Bian W.J, Zhang L.Q, Li Y.H, Long L, Liu X, Zhang X.W, Li Z.G. Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA. Chin. Med. J. 2020;133:679–686.
  • 27. Mäkitie R.E, Kämpe A, Costantini A, Alm J.J, Magnusson P, Mäkitie O. Biomarkers in WNT1 and PLS3 osteoporosis: Altered concentrations of DKK1 and FGF23. J. Bone Miner. Res. 2020;35: 901–912.
  • 28. Capulli M, Paone R & Rucci N. Osteoblast and osteocyte: games without frontiers. Archives of Biochemistry and Biophysics 2014;561:3–12. https://doi.org/10.1016/j.abb.2014.05.003
  • 29. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM & Atkins GJ. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One 2011;6(10):e25900. (https://doi.org/10.1371/journal.pone.0025900).
  • 30. Allison H, Holdsworth G & Mcnamara LM. Scl-Ab reverts proosteoclastogenic signalling and resorption in estrogen deficient osteocytes. BMC Molecular and Cell Biology, 2020, 21 78. (https://doi. org/10.1186/s12860-020-00322-w)
  • 31. Dobbs MB, Buckwalter J & Saltzman C. Osteoporosis: The increasing role of the orthopaedist. Iowa Orthopaedic Journal, 1999; 19:43–52.
  • 32. Mcclung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, et al. Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine 2006;354:821–831. (https://doi. org/10.1056/NEJMoa044459)
  • 33. Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, De Gregorio LH, Hadji P, Hofbauer LC, Álvaro-Gracia JM, Wang H, et al. Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: a Randomized, Blinded, Phase 3 Trial. Journal of Bone and Mineral Research 2009;24:153–161. (https://doi.org/10.1359/jbmr.0809010)
  • 34. Leder BZ, O'dea LSL, Zanchetta JR, Kumar P, Banks K, Mckay K, Lyttle CR & Hattersley G. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. Journal of Clinical Endocrinology and Metabolism 2015;100:697–706. (https://doi.org/10.1210/ jc.2014-3718)
  • 35. Yu EW, Kumbhani R, Siwila-Sackman E, Delelys M, Preffer FI, Leder BZ & Wu JY. Teriparatide (PTH 1–34) treatment increases peripheral hematopoietic stem cells in postmenopausal women. Journal of Bone and Mineral Research 2014;29:1380–1386. (https://doi.org/10.1002/jbmr.2171)
  • 36. Lewiecki EM, Blicharski T, Goemaere S, Lippuner K, Meisner PD, Miller PD, Miyauchi A, Maddox J, Chen L & Horlait S. A. Phase III randomized placebo-controlled trial to evaluate efficacy and safety of Romosozumab in men with osteoporosis. Journal of Clinical Endocrinology and Metabolism 2018;103: 3183–3193. (https://doi.org/10.1210/jc.2017-02163)
  • 37. Glorieux FH, Devogelaer JP, Durigova M, Goemaere S, Hemsley S, Jakob F, Junker U, Ruckle J, Seefried L & Winkle PJ. BPS804 Anti-Sclerostin antibody in Adults with Moderate Osteogenesis imperfecta: results of a Randomized Phase 2a Trial. Journal of Bone and Mineral Research 2017;32:1496–1504. (https://doi.org/10.1002/jbmr.3143)
  • 38. Zhang J, Chen H, Leung RKK, Choy KW, Lam TP, Ng BKW, Qiu Y, Feng JQ, Cheng JCY & Lee WYW Aberrant miR-145–5p/β-catenin signal impairs osteocyte function in adolescent idiopathic scoliosis. FASEB Journal 2018;32 fj201800281. (https://doi.org/10.1096/fj.201800281).
  • 39. Eda H, Santo L, Wein MN, Hu DZ, Cirstea DD, Nemani N, Tai YT, Raines SE, Kuhstoss SA, Munshi NC, et al. Regulation of sclerostin expression in multiple myeloma by Dkk-1; a potential therapeutic strategy for myeloma bone disease. Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research 2016;31:1225–1234. (https://doi.org/10.1002/jbmr.2789)
  • 40. Colucci S, Brunetti G, Oranger A, Mori G, Sardone F, Specchia G, Rinaldi E, Curci P, Liso V, Passeri G, et al. Myeloma cells suppress osteoblasts through sclerostin secretion. Blood Cancer Journal 2011;1 e27. (https://doi. org/10.1038/bcj.2011.22)
  • 41. McDonald MM, Reagan MR, Youlten SE, Mohanty ST, Seckinger A, Terry RL, Pettitt JA, Simic MK, Cheng TL, Morse A, et al. Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma. Blood 2017;129:3452–3464. (https://doi.org/10.1182/blood-2017-03-773341)
  • 42. Atkinson EG & Delgado‐Calle J. The emerging role of osteocytes in cancer in bone. JBMR Plus 2019;3:e10186. (https://doi.org/10.1002/ jbm4.10186).
  • 43. Liu H, He J, Bagheri-Yarmand R, Li Z, Liu R, Wang Z, Bach DH, Huang YH, Lin P, Guise TA, et al. Osteocyte CIITA aggravates osteolytic bone lesions in myeloma. Nature Communications 2022;13:3684. (https://doi. org/10.1038/s41467-022-31356-7)
  • 44. Delgado-Calle J, Anderson J, Cregor MD, Hiasa M, Chirgwin JM, Carlesso N, Yoneda T, Mohammad KS, Plotkin LI, Roodman GD, et al. Bidirectional Notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma. Cancer Research 2016;76: 1089–1100. (https://doi.org/10.1158/0008-5472.CAN-15-1703
  • 45. Mabille C, Ruyssen-Witrand A, Degboe Y, Gennero I, Loiseau HA, Roussel M, Hebraud B, Nigon D, Attal M & Laroche M. DKK1 and sclerostin are early markers of relapse in multiple myeloma. Bone 2018;113:114–117. (https://doi.org/10.1016/j.bone.2017.10.004)
  • 46. Lawson MA, Paton-Hough JM, Evans HR, Walker RE, Harris W, Ratnabalan D, Snowden JA & Chantry AD. NOD/SCID-gamma mice are an ideal strain to assess the efficacy of therapeutic agents used in the treatment of myeloma bone disease. PLoS One 2015;10e0119546. (https://doi.org/10.1371/journal.pone.0119546)
  • 47. Witcher PC, Miner SE, Horan DJ, Bullock WA, Lim KE, Kang KS, Adaniya AL, Ross RD, Loots GG & Robling AG. Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI Insight 2018;3e98673. (https://doi.org/10.1172/jci.insight.98673).
  • 48. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'agostin D, Kurahara C, Gao Y, Cao J, Gong J, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. Journal of Bone and Mineral Research 2008;23:860–869. (https://doi.org/10.1359/ jbmr.080216)
  • 49. Koide M, Yamashita T, Nakamura K, Yasuda H, Udagawa N & Kobayashi Y. Evidence for the major contribution of remodeling-based bone formation in sclerostin-deficient mice. Bone 2022;160:116401. (https://doi. org/10.1016/j.bone.2022.116401)
  • 50. Dreyer T, Shah M, Doyle C, Greenslade K, Penney M, Creeke P, Kotian A, Ke HZ, Naidoo V & Holdsworth G. Recombinant sclerostin inhibits bone formation in vitro and in a mouse model of sclerosteosis. Journal of Orthopaedic Translation 2021;29:134–142. (https://doi.org/10.1016/j. jot.2021.05.005)
  • 51. Akkiraju H & Nohe A. Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. Journal of Developmental Biology 2015;3:177–192. (https://doi.org/10.3390/jdb3040177)
  • 52. Yamaguchi Y, Kumagai K, Imai S, Miyatake K & Saito T. Sclerostin is upregulated in the early stage of chondrogenic differentiation, but not required in endochondral ossification in vitro. PLoS One 2018;13:e0201839. (https://doi.org/10.1371/journal.pone.0201839)
  • 53. Lei Y, Fu X, Li P, Lin S, Yan Q, Lai Y, Liu X, Wang Y, Bai X, Liu C, et al. LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice. Bone Research 2020; 8 :37. (https://doi.org/10.1038/s41413-020- 00108-y)
  • 54. Lu J, Ji ML, Zhang XJ, Shi PL, Wu H, Wang C & Im HJ. MicroRNA218-5p as a potential target for the treatment of human osteoarthritis. Molecular Therapy 2017;25:2676–2688. (https://doi.org/10.1016/j. ymthe.2017.08.009)
  • 55. Wu L, Guo H, Sun K, Zhao X, MA, Ma T & Jin Q. Sclerostin expression in the subchondral bone of patients with knee osteoarthritis. International Journal of Molecular Medicine 2016;38:1395–1402. (https://doi. org/10.3892/ijmm.2016.2741)
  • 56. Li J, Xue J, Jing Y, Wang M, Shu R, Xu H, Xue C, Feng J, Wang P & Bai D. SOST deficiency aggravates osteoarthritis in mice by promoting sclerosis of subchondral bone. BioMed Research International 2019a, 7623562. (https://doi.org/10.1155/2019/7623562)
  • 57. Zhao X, Ma L, Guo H, Wang J, Zhang S, Yang X, Yang L & Jin Q. Osteoclasts secrete leukemia inhibitory factor to promote abnormal bone remodeling of subchondral bone in osteoarthritis. BMC Musculoskeletal Disorders 2022;23:87. (https://doi.org/10.1186/s12891-021-04886-2)
  • 58. Swanson C, Shea S.A, Wolfe P, Markwardt S, Cain S.W, Munch M, Czeisler C.A, Orwoll, E.S, Buxton O.M. 24-hour profile of serum sclerostin and its association with bone biomarkers in men. Osteoporos Int. 2017; 28(11):3205-3213. https://doi.org/10.1007/s00198-017-4162-5
  • 59. Ralston S.H, Corral-Gudino L, Cooper C, Francis R.M, Fraser W.D, Gennari L, Guañabens N, Javaid M.K, Layfield R, O’Neill T.W, et al. Diagnosis and management of Paget’s disease of bone in adults: A clinical guideline. J. Bone Miner. Res. 2019;34:579–604. https://doi.org/10.1002/jbmr.3657
  • 60. Yavropoulou M.P, van Lierop A.H, Hamdy N.A, Rizzoli R, Papapoulos S.E. Serum sclerostin levels in Paget’s disease and prostate cancer with bone metastases with a wide range of bone turnover. Bone 2012;51:153–157. https://doi.org/10.1016/j.bone.2012.04.016
  • 61. Fuentes-Calvo I, Usategui-Martín R, Calero-Paniagua I, Moledo-Pouso C, García-Ortiz L, Pino-Montes J.D, González-Sarmiento R, Martínez-Salgado C. Influence of angiogenic mediators and bone remodelling in Paget’s disease of bone. Int. J. Med. Sci. 2018;15:1210–1216. https://doi.org/10.7150/ijms.26580
  • 62. Catalano A, Bellone F, Morabito N, Corica F. Sclerostin and vascular pathophysiology. Int.J.Mol.Sci. 2020;21:4779. https://doi.org/10.3390/ijms21134779
  • 63. Boltenstål H, Qureshi A.R, Behets G.J, Lindholm B, Stenvinkel P, D’Haese P.C, Haarhaus M. Association of serum sclerostin with bone sclerostin in chronic kidney disease is lost in glucocorticoid treated patients. Calcif. Tissue Int. 2019;104:214–223. https://doi.org/10.1007/s00223-018-0491-4.
  • 64. Nakagawa Y, Komaba H, Hamano N, Tanaka H, Wada T, Ishida H, Nakamura M, Takahashi H, Takahashi Y, Hyodo T, et al. Interrelationships between sclerostin, secondary hyperparathyroidism, and bone metabolism in patients on hemodialysis. J. Clin. Endocrinol. Metab. 2022;107, e95–e105. https://dx.doi.org/10.1210/clinem/dgab623.
  • 65. Fuusager G, Milandt N, Shanbhogue V.V, Hermann A.P, Schou A.J, Christesen H.T. Lower estimated bone strength and impaired bone microarchitecture in children with type 1 diabetes. BMJ Open Diabetes Res. Care 2020;8, e001384. https://doi.org/10.1136/bmjdrc-2020-001384.
  • 66. Cipriani C, Colangelo L, Santori R, Renella M, Mastrantonio M, Minisola S, Pepe J. The interplay between bone and glucose metabolism. Front. Endocrinol. 2020;11:122. https://doi.org/10.3389/fendo.2020.00122.
  • 67. Wedrychowicz A, Sztefko K, Starzyk J.B. Sclerostin and its significance for children and adolescents with type 1 diabetes mellitus (T1D). Bone 2019;120:387–392. https://doi.org/10.1016/j.bone.2018.08.007
  • 68. Yamamoto M, Yamauchi M, Sugimoto T. Elevated sclerostin levels are associated with vertebral fractures in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 2013;98:4030–4037. https://doi.org/10.1210/jc.2013-2143.
  • 69. van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, et al. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. Journal of Bone and Mineral Research, 2007;22(1):19-28. https://doi.org/ 10.1359/jbmr.061002.
  • 70. Diao X, Li Z, An B, Xin H, Wu Y, Li K, et al. The Microdamage and Expression of Sclerostin in Peri-implant Bone under One-time Shock Force Generated by Impact. Scientific Reports, 2017;7(1):6508. https://doi.org/10.26599/NRE.2022.9120011.
  • 71. Ergunol E, Semsi R, Dayanır D, Akgün R.O, Ekim O, Uludamar A, Ozkul A, Sepici-Dinçel A. The local use of sclerostın and dıckoppf-1 as a therapeutıc composıtıon to ıncreaseosseoıntegratıon at alveolar bone graftıng. Clin Chem Lab Med 2023; 61:87-222. https:// doi.org/10.1515/cclm-2023-7046.

Sklerostin ve Wnt Sinyal Yolu Arasındaki İlişki

Yıl 2024, Cilt: 33 Sayı: 3, 186 - 197, 30.09.2024

Öz

Sklerostin, kemik metabolizmasında ve iskelet bozukluklarında önemli rol oynayan bir glikoproteindir. Omurgalılar arasında yüksek oranda korunmuş olan SOST geninden üretilir. Sklerostin üreten kemik hücreleri olan osteositler, bu proteini osteoblastlardaki kanonik Wnt sinyal yolunu antagonize etmek için kullanır. Bu yol, osteoblastların çoğalmasını, farklılaşmasını ve hayatta kalmasını desteklediği için kemik oluşumu için gereklidir. Bununla birlikte, sklerostin bu yolu inhibe ettiğinde, yeni kemik dokusu üretimini azaltır. Hayvanlar üzerinde yapılan çalışmalar, mekanik yüklemenin SOST gen ekspresyonunu azaltarak osteositlerde sklerostin sentezini azaltabileceğini göstermiştir. Bu, kemikler egzersiz veya ağırlık kaldırma gibi mekanik strese maruz kaldığında, SOST geninin ifadesinin azaldığı ve sklerostin üretiminde bir azalmaya yol açtığı anlamına gelir. Bu azalma da Wnt sinyalinin ve kemik oluşumunun artmasını sağlar. Tersine, uzun süreli hareketsizlik dönemlerinde olduğu gibi mekanik yük ortadan kalktığında, sklerostin sentezi artarak kemik oluşumunda azalmaya yol açar. Sklerostinin kemik oluşumunu engellemesi, yüksek kemik kütlesine sahip çeşitli hastalıklarla ilişkilendirilmiştir. Örneğin sklerostin eksikliği, kemik yoğunluğunun ve kalınlığının artmasıyla karakterize nadir bir genetik bozukluk olan sklerosteoza yol açar. Benzer şekilde, van Buchem hastalığı olarak bilinen başka bir nadir genetik bozukluk, SOST genindeki bir mutasyondan kaynaklanır ve bu da sklerostin üretiminde bir azalmaya ve kemik yoğunluğunun artmasına neden olur. Bu derleme, Wnt sinyalizasyonunun temellerini, kemik metabolizması ve iskelet bozukluklarındaki rolünü tartışmaktadır. Ayrıca kemik sağlığını etkileyen iki yaygın durum olan osteoporoz ve osteoartritte Wnt sinyalinin klinik önemini ve gelecekteki etkilerini de değerlendirmektedir. Genel olarak, sklerostin ve Wnt sinyalizasyonunun karmaşık mekanizmalarını anlamak, kemikle ilgili hastalıklar için yeni tedaviler geliştirmek ve kemik sağlığını iyileştirmek için çok önemlidir

Kaynakça

  • 1. Cavalier E, Eastell R, Jørgensen N.R, et al. A Multicenter Study to Evaluate Harmonization of Assays for C-Terminal Telopeptides of Type I Collagen (ß-CTX): A Report from the IFCC-IOF Committee for Bone Metabolism (C-BM). Calcif Tissue Int 2021;08:785–797. https://doi.org/10.1007/s00223-021-00816-5
  • 2. Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin. Genet. 2003;63:192–197. https://doi.org/10.1034/j.1399-0004.2003.00036.x.
  • 3. Van Buchem F, Hadders H, Hansen J, Woldring M. Hyperostosis corticalis generalisata: Report of seven cases. Am. J. Med. 1962;33:387–397. https://doi.org/10.1016/0002-9343(62)90235-8.
  • 4. Lewiecki EM. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis. 2014;6(2):48–57. https://doi.org/10.1177/1759720x13510479
  • 5. Semenov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. 2005;280(29):26770–5. https://doi.org/10.1074/jbc.M504308200.
  • 6. Evenity MG HCP English—Amgen. Available online: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/evenity/evenity_mg_hcp_english.ashx. (accessed on 28 November 2021).
  • 7. European Medicines Agency. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/evenity (accessed on 28 November 2021).
  • 8. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 2001;10:537–544. https://doi.org/10.1093/hmg/10.5.537.
  • 9. Van Hul W, Balemans W, Van Hul E, Dikkers FG, Obee H, Stokroos RJ, Hildering P, Vanhoenacker F, Van Camp G, Willems PJ: Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am J Hum Genet 1998; 62: 391–399.
  • 10. Winkler DG, Yu C, Geoghegan JC, Ojala EW, Skonier JE, Shpektor D, et al. Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex. J Biol Chem 2004;279:36293–8. Httos://doi.org/10.1074/jbc.M400521200
  • 11. Veverka V, Henry A.J, Slocombe P.M, Ventom A, Mulloy B, Muskett F.W, Muzylak M, Greenslade K, Moore A, Zhang L, et al. Characterization of the structural features and interactions of sclerostin. J. Biol. Chem. 2009;284:10890–10900. https://doi.org/10.1074/jbc.M807994200
  • 12. Weivoda MM, Youssef SJ, Jo Oursler M. Sclerostin expression and functions beyond the osteocyte. J Bone 2017;96:45–50. https://doi.org/10.1016/j.bone.2016.11.024 30.
  • 13. Pietrzyk B, Smertka M, Chudek J. Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders. Adv Clin Exp Med 2017;26(8):1283–91. https://doi.org/ 10.17219/acem/68739.
  • 14. Sharma-Ghimire P, Chen Z, Sherk V, Bemben D. Sclerostin and parathyroid hormone responses to acute whole-body vibration and resistance exercise in young women. J Bone Miner Metab 2019;37:358–67. https://doi.org/ 10.1007/s00774-018-0933-0 35.
  • 15. Moester MJC, Papapoulos SE, Lowik CWGM, van Bezooijen RL. Sclerostin: current knowledge and future perspectives. Calcif Tissue Int 2010;87:99–107. https://doi.org/ 10.1007/s00223-010-9372-1
  • 16. Bonnet N, Garnero P, Ferrari S. Periostin action in bone. Mol Cell Endocrinol 2016;432:75–82. doi: 10.1016/j.mce.2015.12.014.
  • 17. Bonnet N, Standley KN, Bianchi EN, Stadelmann V, Foti M, Conway SJ, et al. The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity. J Biol Chem 2009;284(51):35939–50. doi: 10.1074/jbc.M109.060335.
  • 18. Maupin K.A, Droscha C.J. & Williams B.O. A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice. Bone Res. 2013;29;1(1):27-71. https://doi.org/10.4248/BR201301004.
  • 19. Sepici Dinçel A, Jorgensen N.S. New Emerging Biomarkers for Bone Disease: Sclerostin and Dickkopf-1 (DKK1).Calcified Tissue Inteernatiol. 2023;112 (2): 243-257. http://doi.org/10.1007/s00223-022-01020-9
  • 20. Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN, Komm BS, et al. Canonical Wnt signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem.2005;280(39):33132–40. https://doi.org/10.1074/jbc.m500608200.
  • 21. Zhang F, Zhao J, Liu X, Linhardt R.J. Interactions between sclerostin and glycosaminoglycans. Glycoconj. J. 2020; 37(1):119-128. https://doi.org/10.1007/s10719-019-09900-3.
  • 22. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of sost/ sclerostin. J Biol Chem 2008;283:5866–75. doi: 10.1074/jbc.M705092200
  • 23. Sharifi M, Ereifej L, Lewiecki EM. Sclerostin and skeletal health. Rev Endocr Metab Disord 2015;16:149–56. https://doi.org/ 10.1007/s11154-015-9311-6.
  • 24. Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375(16):1532–43. https://doi.org/10.1056/NEJMoa1607948.
  • 25. Brandenburg VM, D’Haese P, Deck A, Mekahli D, Meijers B, Neven E, et al. From skeletal to cardiovascular disease in 12 steps–the evolution of sclerostin as a major player in CKD-MBD. Pediatr Nephrol 2016;31:195–206. https:/doi.org/ 10.1007/ s00467-015-3069-7.
  • 26. Liu Y.Y, Wang S.Y, Li Y.N, Bian W.J, Zhang L.Q, Li Y.H, Long L, Liu X, Zhang X.W, Li Z.G. Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA. Chin. Med. J. 2020;133:679–686.
  • 27. Mäkitie R.E, Kämpe A, Costantini A, Alm J.J, Magnusson P, Mäkitie O. Biomarkers in WNT1 and PLS3 osteoporosis: Altered concentrations of DKK1 and FGF23. J. Bone Miner. Res. 2020;35: 901–912.
  • 28. Capulli M, Paone R & Rucci N. Osteoblast and osteocyte: games without frontiers. Archives of Biochemistry and Biophysics 2014;561:3–12. https://doi.org/10.1016/j.abb.2014.05.003
  • 29. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM & Atkins GJ. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One 2011;6(10):e25900. (https://doi.org/10.1371/journal.pone.0025900).
  • 30. Allison H, Holdsworth G & Mcnamara LM. Scl-Ab reverts proosteoclastogenic signalling and resorption in estrogen deficient osteocytes. BMC Molecular and Cell Biology, 2020, 21 78. (https://doi. org/10.1186/s12860-020-00322-w)
  • 31. Dobbs MB, Buckwalter J & Saltzman C. Osteoporosis: The increasing role of the orthopaedist. Iowa Orthopaedic Journal, 1999; 19:43–52.
  • 32. Mcclung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, et al. Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine 2006;354:821–831. (https://doi. org/10.1056/NEJMoa044459)
  • 33. Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, De Gregorio LH, Hadji P, Hofbauer LC, Álvaro-Gracia JM, Wang H, et al. Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: a Randomized, Blinded, Phase 3 Trial. Journal of Bone and Mineral Research 2009;24:153–161. (https://doi.org/10.1359/jbmr.0809010)
  • 34. Leder BZ, O'dea LSL, Zanchetta JR, Kumar P, Banks K, Mckay K, Lyttle CR & Hattersley G. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. Journal of Clinical Endocrinology and Metabolism 2015;100:697–706. (https://doi.org/10.1210/ jc.2014-3718)
  • 35. Yu EW, Kumbhani R, Siwila-Sackman E, Delelys M, Preffer FI, Leder BZ & Wu JY. Teriparatide (PTH 1–34) treatment increases peripheral hematopoietic stem cells in postmenopausal women. Journal of Bone and Mineral Research 2014;29:1380–1386. (https://doi.org/10.1002/jbmr.2171)
  • 36. Lewiecki EM, Blicharski T, Goemaere S, Lippuner K, Meisner PD, Miller PD, Miyauchi A, Maddox J, Chen L & Horlait S. A. Phase III randomized placebo-controlled trial to evaluate efficacy and safety of Romosozumab in men with osteoporosis. Journal of Clinical Endocrinology and Metabolism 2018;103: 3183–3193. (https://doi.org/10.1210/jc.2017-02163)
  • 37. Glorieux FH, Devogelaer JP, Durigova M, Goemaere S, Hemsley S, Jakob F, Junker U, Ruckle J, Seefried L & Winkle PJ. BPS804 Anti-Sclerostin antibody in Adults with Moderate Osteogenesis imperfecta: results of a Randomized Phase 2a Trial. Journal of Bone and Mineral Research 2017;32:1496–1504. (https://doi.org/10.1002/jbmr.3143)
  • 38. Zhang J, Chen H, Leung RKK, Choy KW, Lam TP, Ng BKW, Qiu Y, Feng JQ, Cheng JCY & Lee WYW Aberrant miR-145–5p/β-catenin signal impairs osteocyte function in adolescent idiopathic scoliosis. FASEB Journal 2018;32 fj201800281. (https://doi.org/10.1096/fj.201800281).
  • 39. Eda H, Santo L, Wein MN, Hu DZ, Cirstea DD, Nemani N, Tai YT, Raines SE, Kuhstoss SA, Munshi NC, et al. Regulation of sclerostin expression in multiple myeloma by Dkk-1; a potential therapeutic strategy for myeloma bone disease. Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research 2016;31:1225–1234. (https://doi.org/10.1002/jbmr.2789)
  • 40. Colucci S, Brunetti G, Oranger A, Mori G, Sardone F, Specchia G, Rinaldi E, Curci P, Liso V, Passeri G, et al. Myeloma cells suppress osteoblasts through sclerostin secretion. Blood Cancer Journal 2011;1 e27. (https://doi. org/10.1038/bcj.2011.22)
  • 41. McDonald MM, Reagan MR, Youlten SE, Mohanty ST, Seckinger A, Terry RL, Pettitt JA, Simic MK, Cheng TL, Morse A, et al. Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma. Blood 2017;129:3452–3464. (https://doi.org/10.1182/blood-2017-03-773341)
  • 42. Atkinson EG & Delgado‐Calle J. The emerging role of osteocytes in cancer in bone. JBMR Plus 2019;3:e10186. (https://doi.org/10.1002/ jbm4.10186).
  • 43. Liu H, He J, Bagheri-Yarmand R, Li Z, Liu R, Wang Z, Bach DH, Huang YH, Lin P, Guise TA, et al. Osteocyte CIITA aggravates osteolytic bone lesions in myeloma. Nature Communications 2022;13:3684. (https://doi. org/10.1038/s41467-022-31356-7)
  • 44. Delgado-Calle J, Anderson J, Cregor MD, Hiasa M, Chirgwin JM, Carlesso N, Yoneda T, Mohammad KS, Plotkin LI, Roodman GD, et al. Bidirectional Notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma. Cancer Research 2016;76: 1089–1100. (https://doi.org/10.1158/0008-5472.CAN-15-1703
  • 45. Mabille C, Ruyssen-Witrand A, Degboe Y, Gennero I, Loiseau HA, Roussel M, Hebraud B, Nigon D, Attal M & Laroche M. DKK1 and sclerostin are early markers of relapse in multiple myeloma. Bone 2018;113:114–117. (https://doi.org/10.1016/j.bone.2017.10.004)
  • 46. Lawson MA, Paton-Hough JM, Evans HR, Walker RE, Harris W, Ratnabalan D, Snowden JA & Chantry AD. NOD/SCID-gamma mice are an ideal strain to assess the efficacy of therapeutic agents used in the treatment of myeloma bone disease. PLoS One 2015;10e0119546. (https://doi.org/10.1371/journal.pone.0119546)
  • 47. Witcher PC, Miner SE, Horan DJ, Bullock WA, Lim KE, Kang KS, Adaniya AL, Ross RD, Loots GG & Robling AG. Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI Insight 2018;3e98673. (https://doi.org/10.1172/jci.insight.98673).
  • 48. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'agostin D, Kurahara C, Gao Y, Cao J, Gong J, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. Journal of Bone and Mineral Research 2008;23:860–869. (https://doi.org/10.1359/ jbmr.080216)
  • 49. Koide M, Yamashita T, Nakamura K, Yasuda H, Udagawa N & Kobayashi Y. Evidence for the major contribution of remodeling-based bone formation in sclerostin-deficient mice. Bone 2022;160:116401. (https://doi. org/10.1016/j.bone.2022.116401)
  • 50. Dreyer T, Shah M, Doyle C, Greenslade K, Penney M, Creeke P, Kotian A, Ke HZ, Naidoo V & Holdsworth G. Recombinant sclerostin inhibits bone formation in vitro and in a mouse model of sclerosteosis. Journal of Orthopaedic Translation 2021;29:134–142. (https://doi.org/10.1016/j. jot.2021.05.005)
  • 51. Akkiraju H & Nohe A. Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. Journal of Developmental Biology 2015;3:177–192. (https://doi.org/10.3390/jdb3040177)
  • 52. Yamaguchi Y, Kumagai K, Imai S, Miyatake K & Saito T. Sclerostin is upregulated in the early stage of chondrogenic differentiation, but not required in endochondral ossification in vitro. PLoS One 2018;13:e0201839. (https://doi.org/10.1371/journal.pone.0201839)
  • 53. Lei Y, Fu X, Li P, Lin S, Yan Q, Lai Y, Liu X, Wang Y, Bai X, Liu C, et al. LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice. Bone Research 2020; 8 :37. (https://doi.org/10.1038/s41413-020- 00108-y)
  • 54. Lu J, Ji ML, Zhang XJ, Shi PL, Wu H, Wang C & Im HJ. MicroRNA218-5p as a potential target for the treatment of human osteoarthritis. Molecular Therapy 2017;25:2676–2688. (https://doi.org/10.1016/j. ymthe.2017.08.009)
  • 55. Wu L, Guo H, Sun K, Zhao X, MA, Ma T & Jin Q. Sclerostin expression in the subchondral bone of patients with knee osteoarthritis. International Journal of Molecular Medicine 2016;38:1395–1402. (https://doi. org/10.3892/ijmm.2016.2741)
  • 56. Li J, Xue J, Jing Y, Wang M, Shu R, Xu H, Xue C, Feng J, Wang P & Bai D. SOST deficiency aggravates osteoarthritis in mice by promoting sclerosis of subchondral bone. BioMed Research International 2019a, 7623562. (https://doi.org/10.1155/2019/7623562)
  • 57. Zhao X, Ma L, Guo H, Wang J, Zhang S, Yang X, Yang L & Jin Q. Osteoclasts secrete leukemia inhibitory factor to promote abnormal bone remodeling of subchondral bone in osteoarthritis. BMC Musculoskeletal Disorders 2022;23:87. (https://doi.org/10.1186/s12891-021-04886-2)
  • 58. Swanson C, Shea S.A, Wolfe P, Markwardt S, Cain S.W, Munch M, Czeisler C.A, Orwoll, E.S, Buxton O.M. 24-hour profile of serum sclerostin and its association with bone biomarkers in men. Osteoporos Int. 2017; 28(11):3205-3213. https://doi.org/10.1007/s00198-017-4162-5
  • 59. Ralston S.H, Corral-Gudino L, Cooper C, Francis R.M, Fraser W.D, Gennari L, Guañabens N, Javaid M.K, Layfield R, O’Neill T.W, et al. Diagnosis and management of Paget’s disease of bone in adults: A clinical guideline. J. Bone Miner. Res. 2019;34:579–604. https://doi.org/10.1002/jbmr.3657
  • 60. Yavropoulou M.P, van Lierop A.H, Hamdy N.A, Rizzoli R, Papapoulos S.E. Serum sclerostin levels in Paget’s disease and prostate cancer with bone metastases with a wide range of bone turnover. Bone 2012;51:153–157. https://doi.org/10.1016/j.bone.2012.04.016
  • 61. Fuentes-Calvo I, Usategui-Martín R, Calero-Paniagua I, Moledo-Pouso C, García-Ortiz L, Pino-Montes J.D, González-Sarmiento R, Martínez-Salgado C. Influence of angiogenic mediators and bone remodelling in Paget’s disease of bone. Int. J. Med. Sci. 2018;15:1210–1216. https://doi.org/10.7150/ijms.26580
  • 62. Catalano A, Bellone F, Morabito N, Corica F. Sclerostin and vascular pathophysiology. Int.J.Mol.Sci. 2020;21:4779. https://doi.org/10.3390/ijms21134779
  • 63. Boltenstål H, Qureshi A.R, Behets G.J, Lindholm B, Stenvinkel P, D’Haese P.C, Haarhaus M. Association of serum sclerostin with bone sclerostin in chronic kidney disease is lost in glucocorticoid treated patients. Calcif. Tissue Int. 2019;104:214–223. https://doi.org/10.1007/s00223-018-0491-4.
  • 64. Nakagawa Y, Komaba H, Hamano N, Tanaka H, Wada T, Ishida H, Nakamura M, Takahashi H, Takahashi Y, Hyodo T, et al. Interrelationships between sclerostin, secondary hyperparathyroidism, and bone metabolism in patients on hemodialysis. J. Clin. Endocrinol. Metab. 2022;107, e95–e105. https://dx.doi.org/10.1210/clinem/dgab623.
  • 65. Fuusager G, Milandt N, Shanbhogue V.V, Hermann A.P, Schou A.J, Christesen H.T. Lower estimated bone strength and impaired bone microarchitecture in children with type 1 diabetes. BMJ Open Diabetes Res. Care 2020;8, e001384. https://doi.org/10.1136/bmjdrc-2020-001384.
  • 66. Cipriani C, Colangelo L, Santori R, Renella M, Mastrantonio M, Minisola S, Pepe J. The interplay between bone and glucose metabolism. Front. Endocrinol. 2020;11:122. https://doi.org/10.3389/fendo.2020.00122.
  • 67. Wedrychowicz A, Sztefko K, Starzyk J.B. Sclerostin and its significance for children and adolescents with type 1 diabetes mellitus (T1D). Bone 2019;120:387–392. https://doi.org/10.1016/j.bone.2018.08.007
  • 68. Yamamoto M, Yamauchi M, Sugimoto T. Elevated sclerostin levels are associated with vertebral fractures in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 2013;98:4030–4037. https://doi.org/10.1210/jc.2013-2143.
  • 69. van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, et al. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. Journal of Bone and Mineral Research, 2007;22(1):19-28. https://doi.org/ 10.1359/jbmr.061002.
  • 70. Diao X, Li Z, An B, Xin H, Wu Y, Li K, et al. The Microdamage and Expression of Sclerostin in Peri-implant Bone under One-time Shock Force Generated by Impact. Scientific Reports, 2017;7(1):6508. https://doi.org/10.26599/NRE.2022.9120011.
  • 71. Ergunol E, Semsi R, Dayanır D, Akgün R.O, Ekim O, Uludamar A, Ozkul A, Sepici-Dinçel A. The local use of sclerostın and dıckoppf-1 as a therapeutıc composıtıon to ıncreaseosseoıntegratıon at alveolar bone graftıng. Clin Chem Lab Med 2023; 61:87-222. https:// doi.org/10.1515/cclm-2023-7046.
Toplam 71 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Cerrahi (Diğer)
Bölüm Derleme
Yazarlar

Rabia Şemsi 0000-0002-8477-5537

Aylin Sepici Dinçel 0000-0001-5847-0556

Erken Görünüm Tarihi 25 Eylül 2024
Yayımlanma Tarihi 30 Eylül 2024
Gönderilme Tarihi 26 Mart 2024
Kabul Tarihi 5 Eylül 2024
Yayımlandığı Sayı Yıl 2024 Cilt: 33 Sayı: 3

Kaynak Göster

AMA Şemsi R, Sepici Dinçel A. Sklerostin ve Wnt Sinyal Yolu Arasındaki İlişki. aktd. Eylül 2024;33(3):186-197.