Jeffrey Gorski, Ph.D
The Gorski lab is focused 1) the mechanism responsible for delamination of teeth after high dose radiation therapy of the mouth and 2) the mechanism of primary bone formation.
Effects of radiation on oral cancer patients. The acute effect of radiation therapy for oral cancer is to provide an effective curative treatment. However, the long term effect of high dose radiation can be delamination of the teeth, where the enamel cracks off causing substantial discomfort and quality of life issues. Based on initial studies by coworker Mary Walker, xerostomia or loss of saliva does not seem to correlate with delamination. As a result, we are focused on the effects of high dose radiation in combination with or without physiological loading on the structure of the dentin enamel junction, a critical interface for adhesion of the enamel layer to the underlying dentin of the tooth. In particular, our studies are directed to a biochemical and enzymatic analysis of the proteolytic enzymes including matrix metalloproteinases of irradiated teeth. Supported by funds from the National Institute of Dental and Craniofacial Research.
Background: the need for new, quicker ways to stimulate bone formation and improve bone density. The boney skeleton plays a critical role in health and disease providing a firm base for dentition and is required for bipedal locomotion and articulation of joints needed for normal human life. The strength of the skeleton is dependent upon its mineralized matrix since decreased bone mineral density is a hallmark diagnostic indicator of osteoporosis, a disease associated with seriously impaired mobility and increased life-threatening vertebral and limb fractures. Osteoporosis is a major global health problem afflicting over 2.3 million Americans and costing over $100 billion dollars annually in the U.S. alone. Despite the severity of this problem, only one drug is currently clinically approved [teraparatide (PTH)] by the Federal Drug Administration to increase bone formation and increase bone mineral density in osteoporotic patients, leading to a decreased fracture risk. However, PTH is expensive, effective in less than 80% of cases, and is slow--taking 1-2 years of treatment to increase bone mass by 1-2%, the minimum threshold for x-ray methods. Thus, there is a strong immediate need for new, quicker ways to stimulate bone formation and to improve bone density. To address these needs, the Gorski lab is researching mechanisms which regulate how primary bone is formed and mineralized in vitro and in vivo, and how the rate of primary bone formation can be easily and accurately be measured in vivo.
Use of in vitro bone cell models to identify regulatory mechanisms controlling primary bone formation—Osteoblast/osteocyte cells in culture provide a direct way to investigate the process of bone mineralization. Our work has provided important data which shows that mineralization in culture
occurs first at specialized lipid-protein complexes termed biomineralization foci (BMF). Specifically, we have identified a phosphoprotein biomarker which is deposited extracellularly at pre-BMF sites PRIOR to mineral crystal deposition at these same sites. A survey of healing bone in vivo shows that this relationship occurs in
Use of in vivo mouse bone models to identify regulatory mechanisms controlling primary bone formation. Based on clues obtained from our in vitro osteoblast/osteocyte cell studies, we have targeted SKI-1 (site-1) protease. We hypothesize that SKI-1, an autolytically activated protease, could function both intracellularly in primary bone cells to regulate transcription of key mineralization genes and extracellularly to cleave/activate BMF biomarker phosphoproteins to mediate mineral crystal nucleation. SKI-1 is a Golgi enzyme which is a member of the proprotein convertase family of proteases which activate growth factors and transcription factors. A global knockout of SKI-1 is embryonically lethal. To investigate SKI-1 function in bone, we have begun to knockout SKI-1 function in bone using a Cre LoxP strategy and Cre promoter strains expressed predominantly in osteoprogenitor cells and osteoblast/osteocyte cells. As shown above, initial results indicate that SKI-1 may play several roles in bone development and in primary bone mineralization. Specifically, the SKI-1 knockout mouse shown is half the size of its littermates, displays a shortened kinky tail, a lower limb paralysis, delayed tooth development, and a 7% reduction in whole body bone mineral density at 10 days of age. Ongoing characterization of the SKI-1 cKO phenotype should help to determine the mechanistic role(s) of SKI-1 in embryonic bone, muscle, and nerve formation, as well as in healing and repair in adults.