, Volume 469, Issue 10, pp 2915-2924
Date: 18 May 2011

Delayed Fracture Healing in Growth Differentiation Factor 5-deficient Mice: A Pilot Study

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Growth differentiation factor-5 (GDF-5) is a key regulator of skeletogenesis and bone repair and induces bone formation in spinal fusions and nonunion applications by enhancing chondrocytic and osteocytic differentiation and stimulating angiogenesis. Elucidating the contribution of GDF-5 to fracture repair may support its clinical application in complex fractures.


We therefore asked whether the absence of GDF-5 during fracture repair impaired bone healing as assessed radiographically, histologically, and mechanically.


In this pilot study, we performed tibial osteotomies on 10-week-old male mice, stabilized by intramedullary and extramedullary nailing. Healing was assessed radiographically and histologically on Days 1 (n = 1 wild-type; n = 5 bp [brachopodism]), 5 (n = 3 wild-type; n = 3 bp), 10 (n = 6 wild-type; n = 3 bp), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 7 wild-type; n = 6 bp), and 56 (n = 6 wild-type; n = 6 bp) after fracture. After 10 (n = 7 wild-type; n = 7 bp contralateral and n = 3 bp fractured tibiae), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 6 wild-type; n = 3 bp), and 56 (n = 8 wild-type; n = 6 bp) days, the callus cross-sectional area was calculated. We characterized the mechanical integrity of the healing fracture by yield stress and Young’s modulus at 28 (n = 6 wild-type; n = 3 bp) and 56 (n = 8 wild-type; n = 6 bp) days postfracture.


The absence of GDF-5 impaired cartilaginous matrix deposition in the callus and reduced callus cross-sectional area. After 56 days, the repaired bp fracture was mechanically comparable to that of controls.


Although GDF-5 deficiency did not compromise long-term fracture healing, a delay in cartilage formation and remodeling supports roles for GDF-5 in the early phase of bone repair.

Clinical Relevance

Local delivery of GDF-5 to clinically difficult fractures may simulate cartilage formation in the callus and support subsequent remodeling.

One or more of the authors (RT) received funding from National Institutes of Health grant ZO1 AR41131.
Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
This work was performed at the Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Service, Bethesda, MD, USA.