Wednesday, March 15, 2000
The investigators will present their scientific papers and results of their research projects at the Orthopaedic Research Society meeting which will precede the AAOS meeting.
The Elizabeth Winston-Lanier Award will be presented to R. Tracy Ballock, MD, for developing a "test tube model of the growth plate that reproduces many of the same features of the growth plate in the body."
Results of these studies with the test tube model demonstrate that thyroid hormone, which is an essential regulator of bone growth in children, works by locally increasing the amount of bone morphogenetic (producing growth) protein in the growth plate and also by modulating the level of proteins associated with the cell division cycle, reported Dr. Ballock.
Dr. Ballock, an assistant professor of orthopaedics and pediatrics at Case Western Reserve University and University Hospitals of Cleveland, Ohio, explained that long bones grow by elongation at either end at the cartilage growth plates. "Somewhat surprisingly," he noted, "the growth plates at the top and bottom of each bone grow at markedly different rates. In order for a person's arms or legs to be the same length, there has to be some coordination of the growth at the growth plates by circulating hormones and local growth factors produced by the growth plates themselves."
Dr. Ballock and associates have focused on identifying the molecular signals that regulate the long bone growth in children. The results from the Ohio study "provide the first glimpse of the molecular pathways used by thyroid hormone to regulate endochondral ossification--the conversion of cartilage to bone--and to establish a new pattern for interpreting the roles of systemic hormones and peptide growth factors in regulating cell growth and differentiation during longitudinal bone growth in children."
The experiments are clinically relevant because the process of endochondral ossification is "arguably the single most important biological pathway in orthopaedics," said Dr. Ballock. This essential series of cellular events is responsible for the development of the skeleton in utero, results in the longitudinal growth of the limbs and trunk, and provides for the regeneration of bone tissue during fracture healing."
By understanding the molecular signals that control this growth process, scientists will be able to devise more rational and specific medical and surgical therapies for abnormal long bone growth and dwarfism that affect children.
Next the researchers will pursue the hypothesis that dietary factors in obese children may interfere with the normal thyroid hormone signals to cause a growth plate disorder known as slipped capital femoral epiphysis (SCFE). In this condition, the ball of the hip joint slips off its attachment to the thighbone. Some children with SCFE can develop a severe crippling form of hip disease for which there is no effective treatment.
Qian Chen, PhD, will receive the Young Investigator Award for his outstanding research on cartilage cell properties in skeletal diseases, including arthritis. Dr. Chen and his associates at Penn State have "identified several molecular markers of cartilage cell (chondrocyte) differentiation and demonstrated that these markers are expressed during skeletal development in the young and during osteoarthritis in older people.
"For a long time, it was very difficult to predict, prevent, or treat osteoarthritis because the mechanism of the disease was not known," he said. "This difficulty stems from the lack of molecular markers of the disease and the lack of characterization of the step-by-step development of the disease." Dr. Chen's Musculoskeletal Research Laboratory at the Pennsylvania State University College of Medicine in Hershey has conducted numerous cell culture experiments and animal studies and "is currently focusing on the regulation of the expression of proteins. If the researchers could determine how to inhibit the synthesis of these markers, they could potentially regulate or even prevent osteoarthritis which affects millions of Americans," he said.
During the study of molecular regulation of chondrocyte differentiation, Dr. Chen and associates discovered that the "two key transitional points during the pathway, from proliferation to maturation, and from maturation to hypertrophy, are subject to regulation by mechanical stress and hormonal molecules." An earlier study identified molecular markers that are express during chondrocyte differentiation-proliferation, maturation, and hypertrophy. They also identified "molecular properties of extracellular matrix proteins that are expressed specifically in these stages, including cartilage matrix protein, collagen type X, and type II."
Supported by the National Institute on Aging of NIH and the Arthritis Foundation, the genetic engineering and cell culture studies have provided a significant amount of new information on the chondrocyte differentiation pathway. Their discoveries have revealed underlying mechanisms regulating chondrocyte differentiation" and may contribute to the development of drug therapy that would regulate cellular proliferation and prevent chondrocyte hypertrophy in osteoarthritis."
Ultimately, the research findings may lead to profound implications for future analysis of cartilage health and maintenance, tissue engineering, and prevention and treatment of osteoarthritis."
The Ann Doner Vaughn Award will be presented to Laurence E. Dahners, MD, and Gayle E. Lester, PhD, for laboratory research confirming that ligaments grow and contract throughout the structure of the ligament and not just at the growth plates. This finding opens the way for researchers to devise ways to induce ligament growth in structures that are too tight (contracted) or to tighten tissues that are too lax, said Dr. Dahners, professor of orthopaedic surgery at the University of North Carolina at Chapel Hill. Another possible therapeutic value would be to prevent a joint from getting stiff after an injury or to prevent a joint from becoming too lax after a sprain.
For their study, Dr. Dahners and Dr. Lester, associate professor of orthopaedic surgery and pharmacology, placed markers along the deltoid ligaments of seven five-week-old rabbits and then compared the amount of ligament growth between each set of markers in each rabbit's deltoid ligament. This work "demonstrated that longitudinal ligament growth occurs interstitially rather than at a 'growth plate' or growth region," said Dr. Dahners. In other studies involving rabbits, the researchers concluded "ligament growth is influenced by the application of constant longitudinal mechanical tension to the growing ligament. Mechanical stress seems to play an important rule in modulating growth. As well, the absence of stress has major importance in the development of contracture.
Dr. Dahners explained that ligaments which control joint motion and tendons which connect muscle to bone are made of a fiber called collagen and are in many ways like a rope. There is glue to hold the fibers together in the rope. The rope can shrink or stretch when the fibers slide past each other.
An abundance of evidence supports the hypothesis that changes in ligament length occur through the sliding of discontinuous fibrils past one another, reported Dr. Dahners. "During contracture, the contractile actin cytoskeleton of the fibroblasts is active and presumably provides the motive force in sliding the fibrils past one another while the ligament is shortening, he reported."
Scientists will continue to research the nature of the "interfibrillar bonds" which bind one fibril to another to prevent sliding. As researchers identify ways to change the interfibrillar bonding, they then may be able to develop mechanisms to lengthen or shorten ligaments to treat patients' medical conditions.
In their studies, systemic hormonal factors appeared to influence the growth of ligamentous tissue. However, it was locally mediated by mechanical tension, or lack of tension, which caused an increase or decrease in growth throughout the length of the ligament, reported Dr. Dahners.
|2000 Academy News March 15 Index C|
Last modified 22/February/2000 by IS