Body growth is rapid in infancy but subsequently slows and eventually ceases due to a progressive decline in cell proliferation that occurs simultaneously in multiple organs. We previously showed that this decline in proliferation is driven in part by postnatal down-regulation of a large set of growth-promoting genes in multiple organs. Recently, we sought to explore the potential role of microRNAs in the regulation of this growth-limiting genetic program. Using bioinformatic analysis, we found that target sequences of the miR-29 family of microRNAs were overrepresented among genes that are down-regulated with age in multiple organs. In addition, expression microarray analysis and real-time PCR showed that all members of the miR-29 family, miR-29a, -b, and -c, were strongly up-regulated with age in multiple organs in mice. We next focused on three predicted miR-29 target genes (Igf1, Imp1, and Mest), all of which are growth-promoting and found evidence that all three genes are indeed regulated by miR-29. Taken together, the findings suggest that up-regulation of miR-29 during juvenile life helps orchestrate a juvenile multi-organ genetic program which involves the down-regulation of many growth-promoting genes with age. Therefore, the evidence supports the hypothesis that up-regulation of the miR-29 family of microRNAs serves as one of the regulatory mechanisms that allows rapid proliferation and body growth in early life but then suppresses proliferation, causing the rate of body growth to slow and eventually approach zero in adulthood. Children grow taller because their bones grow longer. This bone elongation occurs at the growth plate, a thin layer of cartilage found near the ends of juvenile bones. Consequently, many of the genes that control human height are expressed in and function in the growth plate. Based on this concept, we developed bioinformatic methods to identify genes that affect human height through local actions in the growth plate. This approach synthesizes data from our expression microarray studies of the growth plate, human disease databases and a mouse knockout phenotype database. In collaboration with other research groups, this analytic approach has been applied to help identify genes that determine human height within loci detected by genome-wide association studies. In other collaborations, this method has been used to help identify human gene deletions that affect stature. Mutations in hundreds of genes that are required for growth plate function give rise to disorders of skeletal growth, including the skeletal dysplasias, in which the bones are short and malformed, causing major disability. In addition to genetic disorders, acquired endocrine, nutritional, or inflammatory disorders can also impair bone growth at the growth plate, resulting in severe short stature. There are multiple endocrine and paracrine factors that promote chondrogenesis at the growth plate, which could potentially be used to treat these disorders. Targeting these growth factors specifically to the growth plate might augment the therapeutic skeletal effect while diminishing undesirable effects on non-target tissues. To develop cartilage-targeting therapy, we sought to identify polypeptides that home to cartilage tissue. We employed a yeast display human antibody library and selected high-affinity binders to matrilin-3, an extracellular matrix protein expressed with high tissue specificity in cartilage. We identified antibody fragments that bind with high affinity to matrilin-3, as well as to cartilage tissue in vitro. In vivo, these antibody fragments homed specifically to cartilage tissue in mice. Coupling these antibody fragments to endocrine and paracrine factors that stimulate chondrogenesis could be used to direct these potent molecules specifically to cartilage tissue and thus has the potential to open up new pharmacological approaches to treat childhood skeletal growth disorders. Many of the mechanisms that regulate mammalian body growth, when disrupted, can contribute to the development of malignancies. We have studied the role of two heparin-binding growth factors, pleiotrophin and midkine, in the regulation both of normal body growth and in the unregulated growth of malignancies. Recently, we measured midkine concentrations in fine-needle aspirate (FNA) samples from benign and malignant thyroid nodules to explore the possibility that midkine measurement might aid in the evaluation of thyroid nodules. Midkine was measured using a high-sensitivity sandwich ELISA and normalized to thyroglobulin concentration in the sample to adjust for tissue content in the aspirate. We found that, in FNA samples, the midkine/thyroglobulin ratio in papillary thyroid cancer was greater than in benign thyroid nodules, raising the possibility that this approach might provide adjunctive diagnostic or prognostic information to complement existing approaches.
Showing the most recent 10 out of 51 publications
