Educational Background: Dr. Frenkel received his D.M.D. in 1986 and his Ph.D. in Biochemistry in 1991 from Hebrew University. Prior to joining the Institute for Genetic Medicine, Dr. Frenkel was an Instructor at the University of Massachusetts Medical Center.

Figure Legend: Histological illustration of the deleterious effect of glucocorticoids on the elaboration of mineralized extracellular matrix in isolated osteoblast cultures. Calcium deposits are demonstrated by red staining (Alizarin Red, mag. X100).

MECHANISMS OF GLUCOCORTICOID-INDUCED OSTEOPOROSIS

Glucocorticoids, widely prescribed for the management of autoimmune and inflammatory diseases inhibit osteoblast function and cause osteoporosis, but the underlying mechanisms are not well understood. We have developed an osteoblast tissue culture model, in which glucocorticoids inhibit progression through a defined commitment stage, resulting in >90% inhibition of collagen accumulation and mineralized extracellular matrix formation. Focusing on this commitment stage we have made the following discoveries, each establishing an independent research endeavor:

A. GSK3ß and the Wnt signaling pathway.
We discovered that glucocorticoids inhibit the PI3-kinase/Akt pathway in osteoblasts undergoing commitment and that this inhibition results in activation of glycogen synthase kinase 3ß (GSK3ß). Consequently, GSK3ß substrates such as c-Myc are hyperphosphrylated and degraded, resulting in attenuation of a differentiation-related cell cycle. Inhibition of the PI3-kinase/Akt pathway and the consequent activation of GSK3ß also lead to inhibition of the Wnt signaling pathway, establishing, against the current dogma, the existence of a PI3-kinase/Akt/GSK3ß/b-catenin/LEF axis under certain physiological conditions. Ongoing studies focus on glucocorticoid targets downstream of GSK3ß and the roles that these targets play in bone metabolism in vivo.

B. Egr2/Krox20
While inhibiting osteoblast function, glucocorticoids suppress expression of the osteoblast marker gene, osteocalcin. We discovered that this inhibition occurs via a cis-acting element of the osteoclacin promoter, which specifically binds a transcription factor called Egr2/Krox20, and that Egr2/Krox20 expression is strongly reduced in glucocorticoid-treated osteoblasts. Ongoing studies aim at mechanisms of glucocorticoid-mediated Egr2/Krox20 repression and the contribution of Egr2/Krox20 to the control of bone mass in vivo.

C. Bone morphogenetic protein-2 (Bmp2)
During the osteoblast commitment stage described above, glucocorticoids inhibit the expression of the Bmp2 gene, which has been linked to bone mass in human populations. Recombinant BMP-2 rescues the commitment-associated cell cycle and mineralization in glucocorticoid-treated osteoblast cultures. Current studies aim at mechanisms underlying the glucocorticoid-mediated repression of Bmp2.

RUNX2 TARGET GENES IN OSTEOBLASTS

Runx2 (a.k.a. Cbfa1 and AML3) is a master transcription factor in osteoblast differentiation. However, it is difficult to explain the function of Runx2 based on its known target genes. We have developed Chromatin Immunoprecipitation (ChIP) Display (CD), a method by which we have already discovered four novel Runx2 target genes in osteoblasts. We are continuing to use CD, as well as alternative methods, to discover additional Runx2 target genes in osteoblasts, and we are testing the role of these genes in osteoblast differentiation and bone formation.

ANDROGEN RECEPTOR AND RUNX2 IN PROSTATE CANCER

The role of the androgen receptor (AR) in prostate cancer initiation and progression is well established. However, as for Runx2 in osteoblasts, there is only limited knowledge of AR target genes that may mediate its role in prostate cancer. We therefore employ ChIP Display to discover AR target genes in prostate cancer cells.

Interestingly, Runx2, otherwise an osteoblast master transcription factor, is ectopically expressed in prostate cancer cells, potentially contributing to the tendency of these cells to metastasize to bone. In addition, Runx2 has been shown to interact with the AR. Therefore, we are also pursuing Runx2 targets genes and investigating mechanisms by which Runx2 contributes to prostate cancer progression.

OSTEOGENIC GROWTH PEPTIDE (OGP)

We are interested in OGP, an alternative translation product of histone H4 genes. OGP is synthesized by translational initiation at the Met85 codon of histone H4. This is facilitated by leaky ribosomal scanning (LRS) through the imperfect canonical initiation codon of H4 genes. Such a mechanism of alternative translation likely occurs in as much as 12% of mammalian genes. In the case of H4, the LRS and the alternative translation of OGP results in increased bone mass. We have demonstrated the mechanism of OGP biosynthesis in tissue culture and addressed the physiological outcome of this phenomenon using transgenic mice. Current studies focus on the mechanisms of action of OGP in bone.

MORE INFORMATION

For publications by Dr. Frenkel and for information about the USC Program in Biomedical & Biological Sciences (PIBBS), visit http://www.usc.edu/programs/pibbs/site/index_005.html

Last Updated: March, 2006