June 2000 Bulletin

Gene data has impact on orthopaedics

Clinicians should build ties to geneticists to uncover etiology of inherited skeletal diseases

By Linda J. Sandell, PhD

The following is an excerpt of the speech which Linda J. Sandell, PhD, gave at the meeting of the Orthopaedic Research Society in Orlando, Fla. in March 2000.

Later this year, the entire human genome will be known — all 3 billion letters and 80,000 genes that make up the DNA code. The NIH and private companies have dedicated great resources to the completion of this project. This information will be processed by specialists in bioinformatics and made available to everyone in the scientific community.

This data will revolutionize the speed at which new molecules can be analyzed and make way for the comparison of complex arrays of gene expression as seen in osteoarthritis, tumors and biologic response to implant materials to name only a few applications.

One of the research initiatives that will prove successful in the future will be an awareness of genetic influences in orthopaedic diseases. We know that it is possible to trace diseases through families, and studies of these families provide valuable clues to hereditary contributions. Already some genetic defects in musculoskeletal diseases related to orthopaedics have been determined to be caused by single genes. For example, the gene for fibrillin-1 is responsible for a large percentage of Marfan’s Syndrome. Multiple epiphyseal dysplasia is caused by mutations in the cartilage genes, COMP and type IX collagen, and type II collagen gene mutations cause Stickler’s Syndrome and a chondrodysplasia associated with early onset osteoarthritis.

However, many of the chronic diseases of the musculoskeletal system are likely to involve more than one gene, or the environmental effects on one or more genes. Even though such studies involve many patients and their families and the genetics are not straightforward, progress has been made. As examples, a gene on chromosome 19, APOE*4, has been associated with osteoporotic hip and wrist fractures; three genes have been associated with the ectopic bone formation disease, multiple hereditary exostosis; studies of large families with idiopathic club foot or scoliosis have shown a genetic linkage, and chromosomes 4,6 and 16 have been linked to osteoarthritis.

I would like to suggest that clinicians begin to recognize and document the genetic history of orthopaedic patients and build ties to geneticists in our communities to eventually uncover the etiology of inherited skeletal diseases providing insights into advanced treatments.

It has also become necessary to expand our connections to other fields of science not necessarily considered within the traditional musculoskeletal area. In the biological field, many of the discoveries that will affect orthopaedic practice and understanding of disease are coming from other fields of investigation. Insight into the gene for achondroplasia developed from studies on fibroblast growth receptor genes by gene knock out and mutation studies that unexpectedly produced short mice. One of the major regulators of growth plate maturation came from studies on hedgehog, a gene involved in embryogenesis.

A hormone responsible for control of bone growth, leptin, is produced in the brain and was previously known to be involved with the maintenance of body weight and fertility. Additionally, the major transcription factor responsible for cartilage development, Sox 9, was found while examining transcription factors controlling sex determination. The result of such basic science research in many different areas combined with a focus on skeletal tissues will provide the discoveries that can be translated into help for patients with musculoskeletal disease.

Many new discoveries in the field of developmental biology are being applied to tissue engineering and repair of musculoskeletal tissues. Therefore, I appeal for more education and interactions between developmental and molecular.

Linda J. Sandell, PhD, is Professor and Director of Research in the Department of Orthopaedic Surgery, and Professor of Cell Biology and Physiology at Washington University School of Medicine, St. Louis, Mo. She is past president of the Orthopaedic Research Society.

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