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Wnt3a Reestablishes Osteogenic Capacity to Bone Grafts from Aged Animals
Philipp Leucht, MD1; Jie Jiang, PhD2; Du Cheng, BS3; Bo Liu, DDS, PhD3; Girija Dhamdhere, PhD3; Mark Yang Fang, BS3; Stefanie D. Monica, BS4; Jonathan J. Urena, BS5; Whitney Cole, BS6; Lane R. Smith, PhD1; Alesha B. Castillo, PhD6; Michael T. Longaker, MD, MBA3; Jill A. Helms, DDS, PhD3
1 Department of Orthopaedic Surgery (P.L., L.R.S.), Stanford School of Medicine, Stanford, CA 94305
2 Department of Bioengineering (J.J.), University of California Los Angeles, Los Angeles, CA 90095
3 Division of Plastic and Reconstructive Surgery (D.C., B.L., G.D., M.Y.F., M.T.L., J.A.H.), Department of Surgery Stanford School of Medicine, Stanford, CA 94305. E-mail address for J.A. Helms: jhelms@stanford.edu
4 Department of Molecular and Cell Biology (S.D.M.), University of California at Berkeley, Berkeley, CA 94720
5 Department of Medicine (J.J.U.), Columbia University College of Physicians and Surgeons, New York, NY 10032
6 Center for Tissue Regeneration, Repair, and Restoration (W.C., A.B.C.), Rehabilitation Research and Development, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
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  • Disclosure statement for author(s): PDF

Philipp Leucht, MD, Jie Jiang, PhD, Du Cheng, BS, and Bo Liu, DDS, PhD contributed equally to the preparation of this article.

Investigation performed at the Department of Orthopaedic Surgery, and Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, California

Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

Copyright © 2013 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2013 Jul 17;95(14):1278-1288. doi: 10.2106/JBJS.L.01502
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Age-related fatty degeneration of the bone marrow contributes to delayed fracture-healing and osteoporosis-related fractures in the elderly. The mechanisms underlying this fatty change are unknown, but they may relate to the level of Wnt signaling within the aged marrow cavity.


Transgenic mice were used in conjunction with a syngeneic bone-graft model to follow the fates of cells involved in the engraftment. Immunohistochemistry along with quantitative assays were used to evaluate Wnt signaling and adipogenic and osteogenic gene expression in bone grafts from young and aged mice. Liposomal Wnt3a protein (L-Wnt3a) was tested for its ability to restore osteogenic potential to aged bone grafts in critical-size defect models created in mice and in rabbits. Radiography, microquantitative computed tomography (micro-CT) reconstruction, histology, and histomorphometric measurements were used to quantify bone-healing resulting from L-Wnt3a or a control substance (liposomal phosphate-buffered saline solution [L-PBS]).


Expression profiling of cells in a bone graft demonstrated a shift away from an osteogenic gene profile and toward an adipogenic one with age. This age-related adipogenic shift was accompanied by a significant reduction (p < 0.05) in Wnt signaling and a loss in osteogenic potential. In both large and small animal models, osteogenic competence was restored to aged bone grafts by a brief incubation with the stem-cell factor Wnt3a. In addition, liposomal Wnt3a significantly reduced cell death in the bone graft, resulting in significantly more osseous regenerate in comparison with controls.


Liposomal Wnt3a enhances cell survival and reestablishes the osteogenic capacity of bone grafts from aged animals.

Clinical Relevance: 

We developed an effective, clinically applicable, regenerative medicine-based strategy for revitalizing bone grafts from aged patients.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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