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The Journal of Bone and Joint Surgery (American) 83:S23-S30 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.

Scientific Article

Growth/Differentiation Factor-5 (GDF-5) and Skeletal Development

Paul Buxton, PhD, Christopher Edwards, BSc, MBBS, MRCP, Charles W. Archer, PhD and Philippa Francis-West, PhD

From Department of Craniofacial Development, King's College London, London, United Kingdom; Department of Rheumatology, Tan Tock Seng Hospital, Singapore; and School of Molecular and Medical Biosciences, University of Wales, Cardiff, United Kingdom
Philippa Francis-West, PhD Paul Buxton, PhD Department of Craniofacial Development, King's College London, Guy's Hospital, St. Thomas Street, London, SE1 9RT, U.K.
Christopher Edwards, BSc, MBBS, MRCP Department of Rheumatology, Tan Tock Seng Hospital, 11, Jalan Tock Seng, Singapore
Charles W. Archer, PhD School of Molecular and Medical Biosciences, University of Wales, Cardiff, CF1 3YF, U.K.
In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the Arthritis and Rheumatism Campaign. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Background: Growth/differentiation factor-5 (GDF-5) has been shown to be essential for normal appendicular skeletal and joint development in humans and mice. In brachypod , a Gdf-5 gene mouse mutant, the defect is first apparent during early chondrogenesis, with the cartilage blastema already reduced in size by E12.5. This defect is associated with changes in the expression of cell surface molecules.

Methods: To understand further how GDF-5 controls cartilage formation, we first mapped the expression of the Gdf-5 gene during skeletal development (please note that the abbreviation for the gene is given in italics and the abbreviation for the protein expressed by the gene is given in capital letters). Subsequently, we over-expressed GDF-5 in the developing chick embryo using a replication competent retrovirus, RCAS(BP). We determined its effects on skeletal development by histological examination and its effects on early growth by autoradiography of proliferating cells. In addition, we examined the effect of GDF-5 on chondrogenic differentiation using micromass and single cell suspension cultures of limb mesenchymal cells.

Results: These studies show that the Gdf-5 gene is expressed in the early cartilage condensation, the perichondrium, and the joint interzone. Over-expression of GDF-5 in chick limb buds, during the condensation stage or later when the skeletal elements have formed, increased the size of the affected elements. In both cases, the increase in size was associated with an increase in cell number and, at later stages, this was correlated with an increase in S-phase cells. In vitro studies showed that GDF-5 could increase cell adhesiveness, and this may be a mechanism through which GDF-5 initiates condensation formation.

Conclusion:These studies show that GDF-5 acts at two stages of skeletal development and by two distinct mechanisms. First, GDF-5 promotes the initial stages of chondrogenesis by promoting cell adhesion, which is consistent with the expression of Gdf-5 in the cartilage condensation. Second, GDF-5 can increase the size of the skeletal elements by increasing proliferation within the epiphyseal cartilage adjacent to its expression within the joint interzone.


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