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Sci Rep. 2018 Jan 8;8(1):119. doi: 10.1038/s41598-017-18375-x.

A WNT protein therapeutic improves the bone-forming capacity of autografts from aged animals.

Chen T1,2, Li J2,3, Córdova LA2,4, Liu B2,5, Mouraret S2,6, Sun Q2,7, Salmon B2,8, Helms J9,10.

Author information

1
Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 400000, China.
2
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA, 94305, USA.
3
State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Disease & Department of Oral Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610007, China.
4
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Chile, Santiago, Chile.
5
Ankasa Regenerative Therapeutics, Inc. 329 Oyster Point Blvd. Suite 3306, South San Francisco, CA, 94080, USA.
6
Department of Periodontology, Service of Odontology, Rothschild Hospital, AP-HP, Paris 7 - Denis, Diderot University, U.F.R. of Odontology, Paris, France.
7
Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, 110001, China.
8
Paris Descartes - Sorbonne Paris Cite University, Dental School, EA2496, Montrouge, France and Dental Medicine Department, Bretonneau Hospital, HUPNVS, AP-HP, Paris, France.
9
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA, 94305, USA. jhelms@stanford.edu.
10
Ankasa Regenerative Therapeutics, Inc. 329 Oyster Point Blvd. Suite 3306, South San Francisco, CA, 94080, USA. jhelms@stanford.edu.

Abstract

Autografts tend to be unreliable in older patients. Some of these age-related skeletal changes appear to be attributable to a decline in endogenous WNT signaling. We used a functional in vivo transplantation assay to demonstrate that the bone-forming capacity of an autograft can be traced back to a Wnt-responsive cell population associated with the mineralized bone matrix fraction of a bone graft. Micro-CT imaging, flow cytometry and quantitative analyses demonstrate that this mineralized fraction declines with age, along with a waning in endogenous Wnt signaling; together these factors contribute to the age-related deterioration in autograft efficacy. Using a lipid formulation to stabilize the hydrophobic WNT3A protein, we demonstrate that osteogenic capacity can be restored by incubating the bone graft ex vivo with WNT3A. Compared to control bone grafts, WNT-treated bone grafts give rise to three times more bone. These preclinical results establish a pivotal role for WNT signaling in the age-related decline of autologous bone grafting efficacy, and demonstrate a means to restore that efficacy via local, transient amplification of endogenous Wnt signaling.

PMID:
29311710
PMCID:
PMC5758817
DOI:
10.1038/s41598-017-18375-x
[Indexed for MEDLINE]
Free PMC Article

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