New Dimensions of Transcriptional Control in the Skeleton

Jane Lian, Ph.D.
Professor, Cell Biology
University of Massachusetts Medical School

Bone tissue forms during development and continually remodels (bone turnover) in the adult through the coordinated activities of distinct cell populations.  Osteoblast lineage cells respond to physiological signals for calcium homeostasis, energy balance and injury/repair.  These bone forming cells progress through stages of differentiation from the proliferating osteoprogenitor, to the surface osteoblast producing ECM and the osteocyte within the mineralized, supporting mechanical properties of bone.  Our research has focused on identifying and understanding the activities of tissue specific transcription factors that drive the osteogenic program to harness their powerful properties for treating genetic and metabolic disorders of bone.  The BMP2 inducible Runx2, Osterix, Hoxa10 and homeodomain proteins serve as bone paradigms for other tissues.  Among their properties include epigenetic bookmarking of target genes in progenitor cells and chromatin remodeling activity to control the onset of differentiation and regulate the timing of expressed genes that characterize osteoblast subpopulations.  In addition, these factors are subject to post-transcriptional mechanisms by microRNA to attenuate their protein levels.  Our mouse models have identified that modest changes in Runx2 functional activity (in the absence of mutations) can contribute to the cleidocranial dysplasia (CCD) phenotypes, and that depletion of Hox and Dlx factors can alter the osteoblast program in the post-natal skeleton.  Most striking are the in vivo anabolic effects on bone by excision of the Dicer enzyme that generates mature microRNAs in osteocalcin positive osteoblasts.  The presentation will include 1) a review of osteoblast biology and the molecular mechanisms regulating osteoblast maturation and activities; 2) examples of clinical applications for targeting transcriptional and epigenetic factors in the skeleton, and 3) a discussion of future possibilities to translational approaches targeting microRNAs.

Last Reviewed
July 2018