Affiliations

Professor, Dentistry

Advisor, Oral Biology PhD Program

Member, CTSI, JCCC Signal Transduction and Therapeutics Program Area

Osteoporosis inflicts significant morbidity and mortality, especially among postmenopausal women. The only anabolic treatment for osteoporosis is daily injections of parathyroid hormone (PTH), an endogenous peptide whose mechanism of action is unknown. This is not trivial because, while PTH is anabolic when given intermittently, it is equally catabolic when given continuously and intermittent PTH greatly increases the relative risk for osteosarcomas in rats. Our working hypothesis is that PTH-activated osteoblasts undergo a cascade of gene expression beginning with primary genes followed by late genes that affect osteoblast differentiation and function. We have identified several PTH-induced primary genes and we are studying a subset of those that are transcription factors because of their potential to mediate late gene expression. E4BP4/NF-IL3, a basic leucine zipper transcriptional repressor, is involved in apoptosis, the anti-inflammatory response, and circadian rhythm regulation. We found that PTH-induced E4BP4 protein binds to and inhibits E4BP4 response element (EBPRE)-containing promoters in osteoblasts. Interestingly, E4BP4 is induced by glucocorticoids and thyroid hormone, which are potent osteotropic hormones that regulate transcription through their respective nuclear receptors. Thus, our interest in E4BP4 extends into the realm of nuclear receptor-activated osteoblast function. Nuclear receptors are also of special interest to us because we found that PTH induces NGFI-B nuclear orphan receptors in vitro and in vivo. Nurr1, Nur77, and NOR-1 are important for cellular differentiation and they target NGFI-B response element (NBRE)-containing promoters. Nurr1 transactivates the promoter of the osteoblast specific gene osteocalcin (OCN), while Nurr1-expressing adenovirus induces OCN mRNA in osteoblasts. We are currently searching for co-activators that interact with NGFI-B proteins in the transactivation of target genes. Overall, our research has implications for the clinical problem of osteoporosis and the basic science problem of transcriptional regulation. We have established valuable collaborations throughout UCLA that will help us in our studies of the molecular cascades during osteoblast differentiation and function.

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