Understanding the intricacies of skeletal development is not only an important aspect of human biology, it is critical to the field of biomedical engineering for the development of novel therapies to treat skeletal disorders.
Human height is a classic polygenic trait that is highly heritable and has been studied for a number of years to provide insight into aspects of human growth and development. Over the years a number of candidate genes have shown to be involved in height determination however, it is still unclear how these genes directly influence height or skeletal growth.
The VCU scientists observed that a targeted mutation in the sperm associated antigen 17 (SPAG17) gene led to skeletal malformations in mice, such as a shortened hind limb length, fused segments of the sternum, and defects in bone mineralization.
"The mouse tells us the relationship between SPAG17 and bone length, which would explain why there is an association with height," explained Jerome Strauss III, M.D., Ph.D., dean of the VCU School of Medicine and co-senior author on the current study.
Interestingly, Dr. Strauss and his team first came across SPAG17 while studying genes that affected male infertility—SPAG17 is involved in sperm motility. After generating a SPAG17 knockout mouse, the researchers expected to observe an infertile muse phenotype.
“It turned out that this animal had other defects that we hadn’t anticipated,” said Maria Teves, Ph.D., postdoctoral researcher in Dr. Strauss’ lab and lead author on the current study. “The animals died within 12 hours of birth, their tibia and femur were shorter than the wild-type mice, and they had skeletal malformations and bone mineralization defects.”
At this point, Dr. Strauss knew he needed some expertise in the area of musculoskeletal biology, so he looked to researchers within the VCU School of Engineering.
“Researchers from Strauss’ lab could see that a problem had occurred, but there are many techniques that we use in biomedical engineering that let us narrow in on what the defect is,” stated Barbara Boyan, Ph.D., dean of the VCU School of Engineering and co-senior author on the study.
Investigators in Dr. Boyan’s lab analyzed the bone shape and embryonic development of the SPAG17 deficient mice, as well as isolated bone cells for growth in culture, to determine if there was any alteration in the cells ability to form bone.
Ultimately, both groups of investigators came to the same conclusion, which was that the bone malformations in the mice were due to the silencing of the SPAG17 gene and that osteoblasts and chondrocytes (bone forming cells) also expressed this gene.
“This was an unexpected finding,” Dr. Boyan said. “It is not a protein that anybody in my field would have thought to look at.”
Both groups were excited about their findings, but emphasized that more research needs to be conducted to fully understand the entire role of SPAG17 in bone development and structure.
“Our findings are very important because they have revealed functions for SPAG17 that extend the role of this gene to regulation of skeletal development, growth, and mineralization,” Dr. Teves explained. “This was just the beginning. The next step is trying to find the mechanisms of why this gene influences skeletal development.”