Top

Published in:

Open Access 01-12-2010 | Research

Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features

Authors: Falk Wehrhan, Peter Hyckel, Jutta Ries, Phillip Stockmann, Emeka Nkenke, Karl A Schlegel, Friedrich W Neukam, Kerstin Amann

Published in: Journal of Translational Medicine | Issue 1/2010

Abstract

Background

Bone-destructive disease treatments include bisphosphonates and antibodies against the osteoclast differentiator, RANKL (aRANKL); however, osteonecrosis of the jaw (ONJ) is a frequent side-effect. Current models fail to explain the restriction of bisphosphonate (BP)-related and denosumab (anti-RANKL antibody)-related ONJ to jaws. Msx-1 is exclusively expressed in craniofacial structures and pivotal to cranial neural crest (CNC)-derived periodontal tissue remodeling. We hypothesised that Msx-1 expression might be impaired in bisphosphonate-related ONJ. The study aim was to elucidate Msx-1 and RANKL-associated signal transduction (BMP-2/4, RANKL) in ONJ-altered and healthy periodontal tissue.

Methods

Twenty ONJ and twenty non-BP exposed periodontal samples were processed for RT-PCR and immunohistochemistry. An automated staining-based alkaline phosphatase-anti-alkaline phosphatase method was used to measure the stained cells:total cell-number ratio (labelling index, Bonferroni adjustment). Real-time RT-PCR was performed on ONJ-affected and healthy jaw periodontal samples (n = 20 each) to quantitatively compare Msx-1, BMP-2, RANKL, and GAPDH mRNA levels.

Results

Semi-quantitative assessment of the ratio of stained cells showed decreased Msx-1 and RANKL and increased BMP-2/4 (all p < 0.05) expression in ONJ-adjacent periodontal tissue. ONJ tissue also exhibited decreased relative gene expression for Msx-1 (p < 0.03) and RANKL (p < 0.03) and increased BMP-2/4 expression (p < 0.02) compared to control.

Conclusions

These results explain the sclerotic and osteopetrotic changes of periodontal tissue following BP application and substantiate clinical findings of BP-related impaired remodeling specific to periodontal tissue. RANKL suppression substantiated the clinical finding of impaired bone remodelling in BP- and aRANKL-induced ONJ-affected bone structures. Msx-1 suppression in ONJ-adjacent periodontal tissue suggested a bisphosphonate-related impairment in cellular differentiation that occurred exclusively jaw remodelling. Further research on developmental biology-related unique features of jaw bone structures will help to elucidate pathologies restricted to maxillofacial tissue.

Available only for authorised users

Reid IR: Osteonecrosis of the jaw: who gets it, and why?. Bone. 2009, 44: 4-10. 10.1016/j.bone.2008.09.012.PubMedCrossRef

Ruggiero SL, Drew SJ: Osteonecrosis of the jaws and bisphosphonate therapy. J Dent Res. 2007, 86: 1013-1021. 10.1177/154405910708601101.PubMedCrossRef

Agis H, Blei J, Watzek G, Gruber R: Is zoledronate toxic to human periodontal fibroblasts?. J Dent Res. 89: 40-45.

Taylor KH, Middlefell LS, Mizen KD: Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br J Oral Maxillofac Surg. 2010, 48 (3): 221-3. 10.1016/j.bjoms.2009.08.030.PubMedCrossRef

Henry D, vonMoos R, Vadhan-Raj S: A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Eur J Can Suppl. 2009, 7 (3): 12-10.1016/S1359-6349(09)72055-5.CrossRef

Stopeck A, Body J, Fujiwara Y: Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: rusults of a randomized phase 3 study. Eur J Can Suppl. 2007, 5 (3): 31-

Trainor PA: Specification and patterning of neural crest cells during craniofacial development. Brain Behav Evol. 2005, 66: 266-280. 10.1159/000088130.PubMedCrossRef

Luan X, Dangaria S, Ito Y, Walker CG, Jin T, Schmidt MK, Galang MT, Druzinsky R: Neural crest lineage segregation: a blueprint for periodontal regeneration. J Dent Res. 2009, 88: 781-791. 10.1177/0022034509340641.PubMedPubMedCentralCrossRef

Chung IH, Yamaza T, Zhao H, Choung PH, Shi S, Chai Y: Stem cell property of postmigratory cranial neural crest cells and their utility in alveolar bone regeneration and tooth development. Stem Cells. 2009, 27: 866-877. 10.1002/stem.2.PubMedPubMedCentralCrossRef

10.

Blin-Wakkach C, Lezot F, Ghoul-Mazgar S, Hotton D, Monteiro S, Teillaud C, Pibouin L, Orestes-Cardoso S, Papagerakis P, Macdougall M: Endogenous Msx1 antisense transcript: in vivo and in vitro evidences, structure, and potential involvement in skeleton development in mammals. Proc Natl Acad Sci USA. 2001, 98: 7336-7341. 10.1073/pnas.131497098.PubMedPubMedCentralCrossRef

11.

Orestes-Cardoso S, Nefussi JR, Lezot F, Oboeuf M, Pereira M, Mesbah M, Robert B, Berdal A: Msx1 is a regulator of bone formation during development and postnatal growth: in vivo investigations in a transgenic mouse model. Connect Tissue Res. 2002, 43: 153-160.PubMedCrossRef

12.

Babajko S, Petit S, Fernandes I, Meary F, LeBihan J, Pibouin L, Berdal A: Msx1 expression regulation by its own antisense RNA: consequence on tooth development and bone regeneration. Cells Tissues Organs. 2009, 189: 115-121. 10.1159/000151748.PubMedCrossRef

13.

Ruhin-Poncet B, Ghoul-Mazgar S, Hotton D, Capron F, Jaafoura MH, Goubin G, Berdal A: Msx and dlx homeogene expression in epithelial odontogenic tumors. J Histochem Cytochem. 2009, 57: 69-78. 10.1369/jhc.2008.951707.PubMedPubMedCentralCrossRef

14.

Houpis CH, Tosios KI, Papavasileiou D, Christopoulos PG, Koutlas IG, Sklavounou A, Alexandridis C: Parathyroid hormone-related peptide (PTHrP), parathyroid hormone/parathyroid hormone-related peptide receptor 1 (PTHR1), and MSX1 protein are expressed in central and peripheral giant cell granulomas of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010, 109 (3): 415-24. 10.1016/j.tripleo.2009.09.026.PubMedCrossRef

15.

Idowu BD, Thomas G, Frow R, Diss TC, Flanagan AM: Mutations in SH3BP2, the cherubism gene, were not detected in central or peripheral giant cell tumours of the jaw. Br J Oral Maxillofac Surg. 2008, 46: 229-230. 10.1016/j.bjoms.2007.04.014.PubMedCrossRef

16.

Miah SM, Hatani T, Qu X, Yamamura H, Sada K: Point mutations of 3BP2 identified in human-inherited disease cherubism result in the loss of function. Genes Cells. 2004, 9: 993-1004. 10.1111/j.1365-2443.2004.00784.x.PubMedCrossRef

17.

Stockmann P, Vairaktaris E, Wehrhan F, Seiss M, Schwarz S, Spriewald B, Neukam FW, Nkenke E: Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer. 2010, 18 (4): 449-60. 10.1007/s00520-009-0688-1.PubMedCrossRef

18.

Wehrhan F, Rodel F, Grabenbauer GG, Amann K, Bruckl W, Schultze-Mosgau S: Transforming growth factor beta 1 dependent regulation of Tenascin-C in radiation impaired wound healing. RadiotherOncol. 2004, 72: 297-303. 10.1016/j.radonc.2004.07.011.

19.

Boyce BF, Xing L: Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008, 473 (2): 139-46. 10.1016/j.abb.2008.03.018.PubMedPubMedCentralCrossRef

20.

Groetz KA, Al-Nawas B: Persisting alveolar sockets-a radiologic symptom of BP-ONJ?. J Oral Maxillofac Surg. 2006, 64: 1571-1572. 10.1016/j.joms.2006.05.041.PubMedCrossRef

21.

Lekic P, Rubbino I, Krasnoshtein F, Cheifetz S, McCulloch CA, Tenenbaum H: Bisphosphonate modulates proliferation and differentiation of rat periodontal ligament cells during wound healing. Anat Rec. 1997, 247: 329-340. 10.1002/(SICI)1097-0185(199703)247:3<329::AID-AR4>3.0.CO;2-P.PubMedCrossRef

22.

Newberry EP, Boudreaux JM, Towler DA: Stimulus-selective inhibition of rat osteocalcin promoter induction and protein-DNA interactions by the homeodomain repressor Msx2. JBiolChem. 1997, 272: 29607-29613.

23.

Dodig M, Kronenberg MS, Bedalov A, Kream BE, Gronowicz G, Clark SH, Mack K, Liu YH, Maxon R, Pan ZZ: Identification of a TAAT-containing motif required for high level expression of the COL1A1 promoter in differentiated osteoblasts of transgenic mice. JBiolChem. 1996, 271: 16422-16429.

24.

Marx RE, Sawatari Y, Fortin M, Broumand V: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg. 2005, 63: 1567-1575. 10.1016/j.joms.2005.07.010.PubMedCrossRef

25.

Ryoo HM, Lee MH, Kim YJ: Critical molecular switches involved in BMP-2-induced osteogenic differentiation of mesenchymal cells. Gene. 2006, 366: 51-57. 10.1016/j.gene.2005.10.011.PubMedCrossRef

26.

Cohen MM: The new bone biology: pathologic, molecular, and clinical correlates. Am J Med Genet A. 2006, 140: 2646-2706.PubMedCrossRef

27.

Favia G, Pilolli GP, Maiorano E: Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: An analysis of 31 cases with confocal laser scanning microscopy. Bone. 2009, 45 (3): 406-13. 10.1016/j.bone.2009.05.008.PubMedCrossRef

28.

Nishida S, Tsubaki M, Hoshino M, Namimatsu A, Uji H, Yoshioka S, Tanimori Y, Yanae M, Iwaki M, Irimajiri K: Nitrogen-containing bisphosphonate, YM529/ONO-5920 (a novel minodronic acid), inhibits RANKL expression in a cultured bone marrow stromal cell line ST2. Biochem Biophys Res Commun. 2005, 328: 91-97. 10.1016/j.bbrc.2004.12.145.PubMedCrossRef

29.

Viereck V, Emons G, Lauck V, Frosch KH, Blaschke S, Grundker C, Hofbauer LC: Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. BiochemBiophysResCommun. 2002, 291: 680-686.

30.

McGonigle JS, Giachelli CM, Scatena M: Osteoprotegerin and RANKL differentially regulate angiogenesis and endothelial cell function. Angiogenesis. 2009, 12: 35-46. 10.1007/s10456-008-9127-z.PubMedCrossRef

31.

Buckle CH, Neville-Webbe HL, Croucher PI, Lawson MA: Targeting RANK/RANKL in the treatment of solid tumours and myeloma. Curr Pharm Des. 16: 1272-1283. 10.2174/138161210791034021.

32.

Lezot F, Coudert A, Petit S, Vi-Fane B, Hotton D, Davideau JL, Kato S, Descroix V, Pibouin L, Berdal A: Does Vitamin D play a role on Msx1 homeoprotein expression involving an endogenous antisense mRNA?. J Steroid Biochem Mol Biol. 2004, 89-90: 413-417. 10.1016/j.jsbmb.2004.03.116.PubMedCrossRef

33.

Galle S, Yanze N, Seipel K: The homeobox gene Msx in development and transdifferentiation of jellyfish striated muscle. Int J Dev Biol. 2005, 49: 961-967. 10.1387/ijdb.052009sg.PubMedCrossRef

34.

Gersch RP, Lombardo F, McGovern SC, Hadjiargyrou M: Reactivation of Hox gene expression during bone regeneration. J Orthop Res. 2005, 23: 882-890. 10.1016/j.orthres.2005.02.005.PubMedCrossRef

35.

Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S: Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007, 22: 1479-1491. 10.1359/jbmr.0707onj.PubMedCrossRef

36.

Stefanik D, Sarin J, Lam T, Levin L, Leboy PS, Akintoye SO: Disparate osteogenic response of mandible and iliac crest bone marrow stromal cells to pamidronate. Oral Dis. 2008, 14: 465-471. 10.1111/j.1601-0825.2007.01402.x.PubMedPubMedCentralCrossRef

37.

Matsubara T, Suardita K, Ishii M, Sugiyama M, Igarashi A, Oda R, Nishimura M, Saito M, Nakagawa K, Yamanaka K: Alveolar bone marrow as a cell source for regenerative medicine: differences between alveolar and iliac bone marrow stromal cells. J Bone Miner Res. 2005, 20: 399-409. 10.1359/JBMR.041117.PubMedCrossRef

Title: Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features
Authors: Falk Wehrhan
Peter Hyckel
Jutta Ries
Phillip Stockmann
Emeka Nkenke
Karl A Schlegel
Friedrich W Neukam
Kerstin Amann
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2010
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/1479-5876-8-96

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2010

Early detection of urothelial premalignant lesions using hexaminolevulinate fluorescence cystoscopy in high risk patients

Treatment combining RU486 and Ad5IL-12 vector attenuates the growth of experimentally formed prostate tumors and induces changes in the sentinel lymph nodes of mice

Exploring the molecular mechanisms underlying the potentiation of exogenous growth hormone on alcohol-induced fatty liver diseases in mice

Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance

The status of clinical trials: Cause for concern

Increased matrix metalloproteinase activation in esophageal squamous cell carcinoma

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials