Yefu Li , MD, PhD, Assistant Professor of Developmental Biology
Research in the Li laboratory focuses on two major interest areas:
Genetic regulation of skeletogenesis
One of the interesting questions in the study of skeletogenesis is how chondrogenesis and osteogenesis are coordinated during endochondral bone development (hypertrophic cartilage replacement by bone). We have been addressing this question by utilizing a mouse mutant strain, osteochondrodystrophy (ocd). The ocd is a spontaneous mutation, and homozygous ocd/ocd mice exhibit a short stature approximately 7 days after birth. Results from histology analysis demonstrated abnormality in growth plates of the mutant mice, such as disorganized proliferating chondrocyte columns, a reduction in numbers of proliferating chondrocytes, a small size of hypertrophic chondrocytes, and a decrease in amount of trabecular bone. This suggests that ocd is a critical genetic factor regulating chondrogenesis and bone formation during the most active phase of skeletal growth. For understanding the nature of the ocd mutation, we established a high-resolution genetic linkage map of the ocd locus and obtained the physical map of the genomic interval including ocd. The interval contains about 1.1 million DNA base pairs. We found the mRNA level of one of the open-reading frames within the genomic interval was dramatically reduced when compared with that of the wild-type littermates. The cDNA and 2 kb upstream DNA sequence of this open-reading frame was sequenced. No simple mutations, such as a point mutation, deletion and insertion, have been identified in the open-reading frame in ocd/ocd mice. We plan to continue our efforts to identify the ocd mutation by direct DNA sequencing of the entire genomic interval of the ocd region.
Pathogenesis of osteoarthritis
It is the general consensus that osteoarthritis (OA) can occur as a result of one or a combination of genetic and nongenetic factors. Regardless of the nature of the factor(s) that initiate the disease, however, the pathological progression of OA follows a consistent pattern: chondrocyte clustering as a result of increased cell proliferation and a general up-regulation of synthetic activity; increased expression of cartilage-degrading proteinases and gradual loss of proteoglycans in the surface region of articular cartilage, followed by type II collagen degradation; appearance of cracks along the articular cartilage surface (termed fibrillation); and formation of fibrocartilage and osteophytes at the periphery of the joint surface. The pathologic progression indicates that there may be a common molecular sequence of events underlying OA progression. We have been using four mouse OA models, two genetic and two non-genetic forms of OA models, to investigate roles of two genes, HTRA1 (high temperature requirement A 1, a serine protease) and DDR2 (discoidin domain receptor 2, a cell membrane tyrosine kinase receptor for native type II collagen) in the pathogenesis of OA. The ultimate goal of this study is to delineate the molecular basis of a possible common molecular sequence of events underneath OA progression.