Skip to main content

Advertisement

SpringerLink
Log in

Pro-osteogenic Effects of WNT in a Mouse Model of Bone Formation Around Femoral Implants

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Wnt signaling maintains homeostasis in the bone marrow cavity: if Wnt signaling is inhibited then bone volume and density would decline. In this study, we identified a population of Wnt-responsive cells as osteoprogenitor in the intact trabecular bone region, which were responsible for bone development and turnover. If an implant was placed into the long bone, this Wnt-responsive population and their progeny contributed to osseointegration. We employed Axin2CreCreERT2/+;R26mTmG/+ transgenic mouse strain in which Axin2-positive, Wnt-responsive cells, and their progeny are permanently labeled by GFP upon exposure to tamoxifen. Each mouse received femoral implants placed into a site prepared solely by drilling, and a single-dose liposomal WNT3A protein was used in the treatment group. A lineage tracing strategy design allowed us to identify cells actively expressing Axin2 in response to Wnt signaling pathway. These tools demonstrated that Wnt-responsive cells and their progeny comprise a quiescent population residing in the trabecular region. In response to an implant placed, this population becomes mitotically active: cells migrated into the peri-implant region, up-regulated the expression of osteogenic proteins. Ultimately, those cells gave rise to osteoblasts that produced significantly more new bone in the peri-implant region. Wnt-responsive cells directly contributed to implant osseointegration. Using a liposomal WNT3A protein therapeutic, we showed that a single application at the time of implant placed was sufficient to accelerate osseointegration. The Wnt-responsive cell population in trabecular bone, activated by injury, ultimately contributes to implant osseointegration. Liposomal WNT3A protein therapeutic accelerates implant osseointegration in the long bone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Davila Castrodad IM et al (2019) Rehabilitation protocols following total knee arthroplasty: a review of study designs and outcome measures. Ann Transl Med 7(Suppl 7):S255

    PubMed  PubMed Central  Google Scholar 

  2. Branemark PI (1983) Osseointegration and its experimental background. J Prosthet Dent 50(3):399–410

    CAS  PubMed  Google Scholar 

  3. Adell R et al (1981) A 15-year study of osseointegrated implants in the treatment of the edentulous jaw. Int J Oral Surg 10(6):387–416

    CAS  Google Scholar 

  4. Heinecke M et al (2018) The proximal and distal femoral canal geometry influences cementless stem anchorage and revision hip and knee implant stability. Orthopedics 41(3):e369–e375

    PubMed  Google Scholar 

  5. Pilliar RM, Lee JM, Maniatopoulos C (1986) Observations on the effect of movement on bone ingrowth into porous-surfaced implants. Clin Orthop Relat Res 208:108–113

    Google Scholar 

  6. Malak TT et al (2016) Surrogate markers of long-term outcome in primary total hip arthroplasty: a systematic review. Bone Jt Res 5(6):206–214

    CAS  Google Scholar 

  7. Ramamurti BS et al (1997) Factors influencing stability at the interface between a porous surface and cancellous bone: a finite element analysis of a canine in vivo micromotion experiment. J Biomed Mater Res 36(2):274–280

    CAS  PubMed  Google Scholar 

  8. Liu Y et al (2019) WNT3A accelerates delayed alveolar bone repair in ovariectomized mice. Osteoporos Int 30:1873–1885

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Rodari G et al (2018) Progressive bone impairment with age and pubertal development in neurofibromatosis type I. Arch Osteoporos 13(1):93

    PubMed  Google Scholar 

  10. Alghamdi HS, van den Beucken JJ, Jansen JA (2014) Osteoporotic rat models for evaluation of osseointegration of bone implants. Tissue Eng C 20(6):493–505

    Google Scholar 

  11. He YX et al (2011) Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: a drill-hole defect model. Bone 48(6):1388–1400

    PubMed  Google Scholar 

  12. Song L et al (2012) Loss of wnt/beta-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes. J Bone Miner Res 27(11):2344–2358

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang X et al (2018) Global transcriptome analysis to identify critical genes involved in the pathology of osteoarthritis. Bone Jt Res 7(4):298–307

    CAS  Google Scholar 

  14. Boyden LM et al (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346(20):1513–1521

    CAS  PubMed  Google Scholar 

  15. Lewiecki EM et al (2019) One year of romosozumab followed by two years of denosumab maintains fracture risk reductions: results of the FRAME Extension Study. J Bone Miner Res 34(3):419–428

    CAS  PubMed  Google Scholar 

  16. Sovak G, Weiss A, Gotman I (2000) Osseointegration of Ti6Al4V alloy implants coated with titanium nitride by a new method. J Bone Jt Surg Br 82(2):290–296

    CAS  Google Scholar 

  17. Workman P et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102(11):1555–1577

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Szot GL, Koudria P, Bluestone JA (2007) Transplantation of pancreatic islets into the kidney capsule of diabetic mice. J Vis Exp. https://doi.org/10.3791/404

    Article  PubMed  PubMed Central  Google Scholar 

  19. Movat HZ (1955) Demonstration of all connective tissue elements in a single section; pentachrome stains. AMA Arch Pathol 60(3):289–295

    CAS  PubMed  Google Scholar 

  20. Leucht P et al (2007) Accelerated bone repair after plasma laser corticotomies. Ann Surg 246(1):140–150

    PubMed  PubMed Central  Google Scholar 

  21. Minear S et al (2010) Wnt proteins promote bone regeneration. Sci Transl Med 2(29):29ra30

    PubMed  Google Scholar 

  22. Kawamoto T, Kawamoto K (2014) Preparation of thin frozen sections from nonfixed and undecalcified hard tissues using Kawamot’s film method (2012). Methods Mol Biol 1130:149–164

    CAS  PubMed  Google Scholar 

  23. Yuan X et al (2018) Biomechanics of immediate postextraction implant osseointegration. J Dent Res 97(9):987–994

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sun Q et al (2019) Improving intraoperative storage conditions for autologous bone grafts: an experimental investigation in mice. J Tissue Eng Regen Med 13(12):2169–2180

    CAS  PubMed  Google Scholar 

  25. Jing W et al (2015) Reengineering autologous bone grafts with the stem cell activator WNT3A. Biomaterials 47:29–40

    CAS  PubMed  Google Scholar 

  26. Popelut A et al (2010) The acceleration of implant osseointegration by liposomal Wnt3a. Biomaterials 31(35):9173–9181

    CAS  PubMed  Google Scholar 

  27. Dhamdhere GR et al (2014) Drugging a stem cell compartment using Wnt3a protein as a therapeutic. PLoS ONE 9(1):e83650

    PubMed  PubMed Central  Google Scholar 

  28. Morrell NT et al (2008) Liposomal packaging generates Wnt protein with in vivo biological activity. PLoS ONE 3(8):e2930

    PubMed  PubMed Central  Google Scholar 

  29. Hoyte DAN (1966) Experimental investigations of skull morphology and growth W.J.L. Felts and R.J. Harrison (eds). Int Rev Gen Exp Zool 2:345–407

    Google Scholar 

  30. Labek G et al (2011) Revision rates after total joint replacement: cumulative results from worldwide joint register datasets. J Bone Jt Surg Br 93(3):293–297

    CAS  Google Scholar 

  31. Sadoghi P et al (2013) Revision surgery after total joint arthroplasty: a complication-based analysis using worldwide arthroplasty registers. J Arthroplast 28(8):1329–1332

    Google Scholar 

  32. Apostu D et al (2018) Current methods of preventing aseptic loosening and improving osseointegration of titanium implants in cementless total hip arthroplasty: a review. J Int Med Res 46(6):2104–2119

    CAS  PubMed  Google Scholar 

  33. Lam YF et al (2016) A review of the clinical approach to persistent pain following total hip replacement. Hong Kong Med J 22(6):600–607

    CAS  PubMed  Google Scholar 

  34. Piscitelli P et al (2013) Painful prosthesis: approaching the patient with persistent pain following total hip and knee arthroplasty. Clin Cases Miner Bone Metab 10(2):97–110

    PubMed  PubMed Central  Google Scholar 

  35. Abu-Amer Y, Darwech I, Clohisy JC (2007) Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies. Arthritis Res Ther 9(Suppl 1):S6

    PubMed  PubMed Central  Google Scholar 

  36. Janssen D et al (2010) Computational assessment of press-fit acetabular implant fixation: the effect of implant design, interference fit, bone quality, and frictional properties. Proc Inst Mech Eng H 224(1):67–75

    CAS  PubMed  Google Scholar 

  37. Soballe K et al (1992) Tissue ingrowth into titanium and hydroxyapatite-coated implants during stable and unstable mechanical conditions. J Orthop Res 10(2):285–299

    CAS  PubMed  Google Scholar 

  38. Nazemi SM et al (2017) Optimizing finite element predictions of local subchondral bone structural stiffness using neural network-derived density–modulus relationships for proximal tibial subchondral cortical and trabecular bone. Clin Biomech (Bristol Avon) 41:1–8

    Google Scholar 

  39. Goltzman D (2019) The aging skeleton. Adv Exp Med Biol 1164:153–160

    CAS  PubMed  Google Scholar 

  40. Salmon B et al (2017) WNT-activated bone grafts repair osteonecrotic lesions in aged animals. Sci Rep 7(1):14254

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Virdi AS et al (2015) Sclerostin antibody treatment improves implant fixation in a model of severe osteoporosis. J Bone Jt Surg Am 97(2):133–140

    Google Scholar 

  42. Pei X et al (2017) Contribution of the PDL to osteotomy repair and implant osseointegration. J Dent Res 96(8):909–916

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Li Z et al (2020) Effects of condensation and compressive strain on implant primary stability: a longitudinal, in vivo, multiscale study in mice. Bone Jt Res 9(2):60–70

    Google Scholar 

Download references

Acknowledgements

We thank Dr. Yindong Liu, Bo Liu, and Dr. Giuseppe Salvi for their contributions to this manuscript. This work was supported by a Grant from the NIH (R01 DE024000-12) to JAH.

Author information

Authors and Affiliations

  1. Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Zhijun Li

  2. Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA, 94305, USA

    Zhijun Li, Xue Yuan, Masaki Arioka, Qiang Sun, Jinlong Chen & Jill A. Helms

  3. Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Masaki Arioka

  4. Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Daniel Bahat

  5. Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, 110001, China

    Qiang Sun

  6. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Jinlong Chen

Authors
  1. Zhijun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xue Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaki Arioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel Bahat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinlong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jill A. Helms
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jill A. Helms.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (JPG 339 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Z., Yuan, X., Arioka, M. et al. Pro-osteogenic Effects of WNT in a Mouse Model of Bone Formation Around Femoral Implants. Calcif Tissue Int 108, 240–251 (2021). https://doi.org/10.1007/s00223-020-00757-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-020-00757-5

Keywords

Search

Navigation