Gene Involved in Bone Mineral Density and Osteoarthritis
One method of studying the cause of disease is to study genetic diseases that result in similar symptoms. One example of this is the study of multiple epiphyseal dysplasia (MED), which results in abnormal bone development and early-onset osteoarthritis. It is known that mutations in the gene encoding matrillin-3, a protein that is abundant in cartilage, are associated with several skeletal diseases, including MED and idiopathic hand osteoarthritis (OA).
What problem was studied?
MED is characterized by delayed and irregular ossification (formation of bone) of the epiphyses (rounded ends of the long bones) in children and early-onset OA. To better understand the pathologic mechanisms of OA development, Arthritis Foundation-funded researcher Qian Chen, PhD, of Brown Medical School in Providence, RI, and other researchers at Brown, Wellcome Trust Genome Campus in Cambridge, United Kingdom, and Thomas Jefferson University in Philadelphia, studied the role of matrillin-3 in cartilage during embryonic development and adulthood.
What was done in the study?
To help understand the function of matrillin-3, the researchers designed their experiment to determine what would happen to growth and development if matrillin-3 were absent. Through gene manipulation and cross-breeding, the research team bred a strain of mice that lacked the gene encoding the matrillin-3 protein (called Matn3 null mice). These mice were healthy at birth, and both males and females were fertile and had a normal lifespan.
What were the study results?
It was found that the null mice showed no gross skeletal malformations and had normal skeletal architecture. Upon more detailed examination, however, it was found that the epiphyseal growth plates of the tibiae in these mice were expanded compared with wild-type mice (mice of the same lineage that did not receive the altered gene). The length of the hypertrophic zone (rapidly growing region) was increased by 47% in the null mice compared with the wild-type ones.
Although the Matn3 null mice showed no obvious abnormalities in bone structure or growth (something that would be seen in MED), the researchers did find that these mice had significantly higher bone mineral density than wild-type mice. Elevated bone mineral density is one feature of osteoarthritis, and the researchers next studied the occurrence of OA in the null mice.
OA of the knee joint was not observed in young mice, but affected 100% of null mice at 1 year of age. In contrast, 45% of wild-type mice had knee OA at 1 year, but of a less severe grade. Therefore, OA occurs with higher incidence and more severity in adult matrillin-3 null mice during aging despite the lack of chondrodysplasia when young.
In summary, this team of researchers has determined that mice that lack the matrillin-3 protein have increased bone mineral density, a higher incidence of osteoarthritis, and develop more severe OA than wild-type mice.
What does this mean for the future of OA research?
The findings of this study showed that deficiency in the protein matrillin-3 results in both an increase in bone mineral density and joint cartilage degeneration, thereby connecting the two events. Furthermore, the development of this strain of mice provides an important animal model to study the relationship between bone and cartilage.
Van der Weyden L, Wei L, Luo J, et al. Functional Knockout of the Matrilin-3 Gene Causes premature Chondrocyte Maturation to Hypertrophy and Increases Bone Mineral Density and Osteoarthritis. Am J Pathol 2006;. 169:515--27.