Michael Centrella PhD
Molecular aspects of bone growth factor and receptor expression and activity; control of protein synthesis initiation
Systemic hormones and local growth factors together regulate bone growth and remodeling. The work in Dr. Michael Centrella's lab examines the mechanisms by which hormones and local bone growth factors control bone cell activity, often through changes in new growth factor or receptor expression. Local bone growth factors also regulate cells in other tissues. Many lines of evidence now predict that hormones and local growth factors often interact to control bone growth in a skeletal tissue specific way. In addition, we examine stress systems that control protein synthesis initiation, linking these events to variations in osteoblast growth and differentiation.
Extensive Research Description
Our lab was the first to identify TGF-beta in bone, to demonstrate differential effects by TGF-beta on parameters associated with osteoblast activity, to visualize TGF-beta receptors on osteoblasts, and to clone and characterize the first detailed set of TGF-beta receptor gene promoter regions from a single species. We were also among the first to define fundamental effects by a panel of other growth factors, including the IGFs, FGFs, PDGFs, and BMPs, and their receptors on osteoblasts. My effort greatly benefits from the knowledge and shared interests of my long term co-investigator Dr. Thomas L. McCarthy and from other highly skilled colleagues at Yale and elsewhere who invest time and effort with our group. One special focus of Dr. McCarthy’s and my lab has been to determine how other agents or events impinge on local growth factor expression or activity. In this way we resolved novel effects by polypeptide and steroid hormones, by load bearing, and by cellular interactions that translate to downstream changes in cell function. We showed that many effects are indirect, through variations in the expression or activity of important trans-acting transcription factors. In this regard, we defined a panel of genes controlled by transcription factors Runx2, an obligate regulator of osteogenesis, and C/EBPdelta, an essential component of the acute phase response. Among other activities, we determined biochemical, molecular, and hormonal regulators of Runx2 and C/EBPdelta expression and activity. We defined novel physical and functional interactions by these factors with steroid hormone receptors and more recently, with downstream components of the Wnt pathway. Because of their important involvement with bone loss and aging, we also developed a special interest in sex steroid metabolism by osteoblasts. In this regard we showed that osteoblasts have the potent capacity to cross convert estrogenic and androgenic compounds, and identified a novel estrogen receptor activator that is produced by differentiated osteoblasts and has partially restricted anabolic effects on these cells. We hope to produce enough of this molecule to determine its structure and establish its value as a possible hormone replacement therapeutic. While we often concentrate on osteoblasts, we developed a parallel focus to learn how growth factors differ in function on cells within or between tissues. We initiated studies and entered collaborations with other leading labs to extend results first observed in osteoblasts to vascular, dermal, heart, tendon, kidney, pulmonary, and tumor cell models.