Dr. Kronenberg’s laboratory uses genetically manipulated mice to study signaling by the PTH/PTHrP receptor, bone development and the regulation of hematopoiesis by cells of the osteoblast lineage. We meet regularly with members of Cliff Tabin’s group to discuss bone-development projects and with David Scadden’s group to discuss projects involving the fates of cells of the osteoblast lineage and the interactions of these cells with hematopoietic cells.
Current projects include:
1. Studies of mice with mutant PTH/PTHrP receptors that signal normally through Gs but cannot activate Gq/11. Jun Guo used “knock-in” technology to generate these mice. They have mild but instructive abnormalities of their growth plates. They are also mildly osteoporotic. When PTH levels are elevated either with a low calcium diet or PTH infusion, they exhibit deficient accumulation of osteoblast precursors and abnormalities in phosphate metabolism.
2. Origin of osteoblasts in the primary spongiosa. Christa Maes used a lineage-tracing strategy to mark a subset of periosteal cells early in bone development that express the osterix gene. By following the fates of these cells, she showed that they and their descendants populate the primary spongiosa. After such cells begin expressing the collagen I(a1) promoter in the perichondrium, they can no longer contribute to the primary spongiosa. Noriaki Ono is now studying analogous mice that use the nestin, smooth muscle actin, and coll2a1 promoters to track the fates of cells of the osteoblast lineage in fetal and postnatal life.
3. Shigeki Nishimori is using mutant mice to establish the hypothesis that PTHrP slows chondrocyte differentiation by activating protein phosphatase IIA with subsequent movement of HDAC4 and HDAC5 into the nucleus and inhibition of the actions of MEF2c and Runx2.
4. Wnt signaling as a mediator of PTH actions. Jun Guo generated mice overexpressing dickkopf-1 (Dkk-1) in osteoblasts and has also established knockout b-catenin in postnatal osteoblasts. With both approaches, the effects of these manipulations on PTH actions are being examined. PTH potentiates wnt signaling, and this probably contributes to the anabolic actions of PTH.
5. Noriaki Ono is trying to isolate chondrocyte stem cells and examine their properties.
6. Marc Wein, in collaboration with Dr. Divieti Pajevic, is examining the pathways by which PTH suppresses sclerostin expression in an osteocyte cell line. With the Broad Institute, he will perform a genome-wide screen of siRNA molecules to comprehensively define the pathway.
7. Hong Mei, in collaboration with David Scadden, has begun to examine the fates of articular chondrocytes in normal mice and in experimental osteoarthritis.
8. Deepak Balani is studying the role of PTH in activating early cells of the osteoblast lineage. He is using genetically marked mice to identify these cells and study PTH action in vivo.
9. Wanida Ono is using lineage tracing and gene knockout technology to study the fetal development of the roots of teeth. She has found that the PTH/PTHrP receptor is essential for normal root development.