Henry Kronenberg, MD
Dr. Kronenberg’s laboratory uses genetically manipulated mice to study signaling by the PTH/PTHrP receptor and bone development. Current projects include the following:
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 also are mildly osteoporotic. When PTH levels are elevated either with low calcium diet or PTH infusion, they exhibit deficient accumulation of osteoblast precursors and abnormalities in phosphate metabolism.
2. Ablation of Gsa in early cells of the osteoblast lineage. Joy Wu, using the cre-lox approach and an osterix promoter-driven cre, generated mice with ablation of Gsa, the subunit of Gs that activates adenylate cyclase. The resultant mice are born with fractures and a major defect in generating B cells.
3. Origin of osteoblasts in the primary spongiosa. Christa Maes has 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 shows 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.
4. Role of PTH/PTHrP receptor signaling in the growth plate postnatally. Takao Hirai and Andre Chagin are using the cre-lox approach to knock the PTH/PTHrP receptor out of the growth plates of postnatal mice. Within several days the growth plates of such mice fuse, thus establishing an essential role for PTH/PTHrP receptor signaling in maintaining the postnatal growth plate.
5. Wnt signaling as a mediator of PTH actions. Jun Guo generated mice overexpressing dickkopf-1 (Dkk-1) in osteoblasts, and has begun to 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.
6. Microarray analysis of the murine newborn growth plate. Shigeki Nishimori used microarray technology to generate a comprehensive list of genes expressed by differing portions of the newborn murine tibial growth plate. These data demonstrate novel genes expressed at each stage of differentiation.
7. Limb bud and heart (LbH), a novel transcription regulator in the growth plate. Katrin Conen took this gene, expresses in hypertrophic chondrocytes in Dr. Nishimori’s experiments and overexpressed it in embryonic chick limbs. The resultant chicks exhibit delays in chondrocyte and osteoblast development that probably reflect suppression of Runx2 and VEGF expression.
8. Role of Par6gamma in bone development. Kwok Tsang is exploring the possible role of par6 isoforms in regulating polarity of osteoblasts, using cell line and the chick embryo expression model.
9. Roles of PTH and PTHrP in fetal calcium metabolism. Tatsuya Kobayashi and Takao Hirai are using mice mutant for PTH, PTHrP, and RANKL to determine the mechanism of the hypocalcemia of prenatal mice missing PTH.
