Bone morphogenetic proteins in the development and healing of synovial joints*,**,

https://doi.org/10.1053/sarh.2001.24875Get rights and content

Abstract

Objectives: To review current knowledge of the role of bone morphogenetic proteins (BMPs) in joint formation and how this may be relevant to healing in adult joints. Method: Review of published literature using a search of the PubMed database (1966 to 2000) made available by the National Library of Medicine. Additional articles of historical interest were identified from the bibliographies of published literature. Results: BMPs and a related family, the growth and differentiation factors (GDFs), are stimulators of bone and cartilage formation in the developing skeleton. They, together with their antagonists, play key roles in the specification of the joint site and cavitation of synovial joints during embryonic development. Disruption of the GDF-5 gene in mice and humans is associated with abnormal joint formation. In situ hybridization studies have shown that BMPs are expressed during formation of synovial joints in the embryo. However, excessive BMP activity leads to obliteration of joints because of cartilage overgrowth. BMPs are being considered as therapeutic agents to stimulate healing of articular cartilage after damage. Evidence suggests that BMPs are present in adult joints and have roles in healing and maintenance. However, inflammatory cytokines and growth factors present in damaged joints modulate the actions of BMPs. Conclusions: BMPs, and in particular GDF-5, are involved in synovial joint formation. They may also have effects on the maintenance and healing of adult joints, but factors present after damage may alter their effectiveness. Relevance: Articular cartilage heals poorly after damage. BMPs may be useful therapeutically to stimulate healing of damaged articular cartilage. Increased knowledge of their role in joint formation will improve understanding of how to use them. Semin Arthritis Rheum 31:33-42. Copyright © 2001 by W.B. Saunders Company

Section snippets

Methods

A review of the published literature using a search of the entire PubMed database made available by the National Library of Medicine was undertaken. The search included articles from 1966 to 2000. Key articles on joint development and BMPs/GDFs were identified, and additional articles of interest were selected from the bibliographies of published literature.

Animal models and human disease

There are a number of syndromes characterized by abnormalities of synovial joints, and recently the gene mutations responsible for a number of these have been identified (Table 1).

Table 1: The Effects of BMP and BMP Inhibitor Gene Mutations on Skeletal Formation in Mice and Humans

BMPDiseaseGene AbnormalityPhenotypeReference No.
Mouse
 GDF-5BrachypodismFrame shiftShort limbs, loss of PIPs, wrist and ankle fusions15, 16
 BMP-5Short ear mouseDeletionShort ears; small, long bones(79)
Human
 GDF-5

Discussion

Joint formation appears to depend on localized and stage-dependent activities of BMPs. In addition, it also depends on surrounding tissues such as the muscles, which themselves may induce changes in gene expression in the developing joint by mechanical stimulation. The expression of BMP antagonists is likely to be a key determinant during joint development suggesting that down-regulation/ablation of BMP activity including GDF-5 is essential for joint development. The actions of BMPs in animal

Acknowledgements

We thank Paul Buxton for providing the radioactive in situ hybridization data, Vicki Church for critically reading the manuscript, and Frank Luyten and Tom Jessel for providing the GDF-5 and chordin complementary DNA probes, respectively.

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    *

    Christopher J. Edwards, MRCP: Lecturer in Rheumatology, The Kennedy Institute of Rheumatology, Imperial College School of Medicine, London, UK; Philippa H. Francis-West, PhD: Reader in Developmental Biology, Department of Craniofacial Development, Kings College London, London, England.

    **

    Supported by the Arthritis Research Campaign.

    Address reprint requests to Dr Christopher Edwards, Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433. E-mail: [email protected]

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