Kristin Evans Graduate Student (Ph.D. Program) Major Professor: Dr. Anita Oberbauer Phone: (530)752-1046 FAX: (530)752-0175 Email: kdmartin@ucdavis.edu

Education: 

B.S., Animal Science, UC Davis, Davis, CA 1997
M.S., Animal Science, UC Davis, Davis, CA 1999
Ph.D., Physiology (Designated Emphasis: Endocrinology), UC Davis, Davis, CA
(In Progress)
D.V.M., UC Davis, Davis, CA (In Progress)

Project

Title: Bisphosphonate Effects on Bone Elongation in the Osteogenesis Imperfecta Mouse Model.

Osteogenesis imperfecta (OI) is a genetic disease affecting the nucleotide coding for Type I collagen. Type I collagen is the main protein structural component of bone, thus the main phenotypic result of the gene defect is the propensity for brittle bones. The defects in the genetic code for the protein prohibit the protein from folding into the necessary tertiary structure, which normally creates sites for mineralization. As a result of decreased mineralization sites within the protein, the bone itself is less mineralized and is subject to fractures. In addition to the decreased mineralization, the body senses the defective collagen and will send in osteoclasts to degrade the defective collagen and replace it. While this normally leads to maintenance of structural integrity, the new collagen is produced from the same defective gene code leading to a never-ending cycle of resorption, which further impairs the structural integrity of the bone. 

The current study proposes that by inhibiting this osteoclast resorption of defective bone, we can increase the structural integrity of the bone and reduce the incidence of fractures. Bisphosphonate drugs are currently used for the treatment of post-menopausal osteoporosis. These drugs inhibit overactive osteoclasts from resorbing bone, which is the underlying cause of the osteoporosis condition. 

The current study proposes the use of bisphosphonates to inhibit osteoclasts in mice with a gene mutation in the collagen Type I gene similar to OI. However, there are some questions as to the adverse effects of bisphosphonate drug use in juvenile growing individuals. Osteoclasts and septoclasts (osteoclast like cells) are imperative to the vascular invasion that initiates growth plate turnover at the junction between growth plate cartilage and new bone. Inhibition of osteoclasts by bisphosphonate drugs could serve to inhibit growth by preventing cell turnover within the growth plate.

The current study will assess in vivo effects of the bisphosphonate drug pamidronate on the growth of long bones in the oim mouse model for OI. Assessment of pamidronate effects on osteoclast chemotaxis will also be studied using bone marrow derived osteoclasts. Expression of osteoclast chemotactic protein signals within each region of the growth plate over time will also be studied to determine the time point in which they peak within the growth phase. 

Overall, these studies will provide more insight into the interaction between bisphosphonate drugs and the growth mechanisms of bone in order to assess their usefulness as a treatment for juvenile bone diseases.