Estrogen‐TGFβ cross‐talk in bone and other cell types: Role of TIEG, Runx2, and other transcription factors

Abstract

It is well established that E 2 and TGFβ have major biological effects in multiple tissues, including bone. The signaling pathways through which these two factors elicit their effects are well documented. However, the interaction between these two pathways and the potential consequences of cross-talk between E 2 and TGFβ continue to be elucidated. In this prospectus, we present known and potential roles of TIEG, Runx2, and other transcription factors as important mediators of signaling between these two pathways. KeywordsBone; Runx2; TIEG; Estrogen; TGFβ; osteoblast; osteoclast Estrogen (E 2 ) and TGFβ are known to be major regulators of skeletal formation and maintenance Spelsberg et al., 1999;Rickard et al., 2002a;Janssens et al., 2005]. In the past there have been numerous reports about the interaction (cross-talk) between these two important regulators, many of which involve transcription factors. This prospectus summarizes some of these studies and proposes some potential areas of crosstalk in osteoblast (OB) cells which includes Runx2 and another important factor discovered by our laboratory, the TGFβ inducible early gene-1 (TIEG), also known as Krüppel-like transcription factor-10 (KLF-10) [Subramaniam et al., 1995]. ESTROGEN ACTION IN OB CELLSThe skeleton is one of the main targets of E 2 action in the body as it regulates bone growth and remodeling. Estrogen has major effects on OB and osteoclast (OC) differentiation, including OB proliferation, differentiation, matrix production, and mineralization [Hughes et al., 1996;Robinson and Spelsberg, 1997;Oursler, 1998;Khosla et al., 1999;Rickard et al., 1999Rickard et al., , 2002aSpelsberg et al., 1999]. Decreased E 2 levels are known to be one of the main causes of osteoporosis [Melton, 1995;Gallagher, 1996] and there is abundant evidence demonstrating a critical role for E 2 in regulating bone metabolism and homeostasis in both [Riggs et al., 2002]. It is important to understand E 2 action in the skeleton to better define the mechanisms of bone loss and in order to develop new approaches to prevent and treat osteoporosis. The primary mechanism by which E 2 elicits its effects on target tissues is by binding to, and activating, the two major estrogen receptor (ER) isoforms, ERα and ERβ. It was originally believed that ERβ only modulated the activity of ERα; however, recent studies by our laboratory and others have demonstrated that these two receptors regulate distinct sets of genes in OBs [Waters et al., 2001;Rickard et al., 2002b;Monroe et al., 2003a;Kian Tee et al., 2004;Stossi et al., 2004;Monroe et al., 2005]. Adding to this complexity is the identification of a host of nuclear receptor co-activators and corepressors that modulate E 2 action [McKenna et al., 1999]. OBs express both ERα and ERβ, and both are differentially expressed during OB maturation. The ERα concentrations in rat OB cells increase by almost 10-fold during the differentiation of OB precursor cells into mature OBs, whereas ERβ concentrations increase only slightly, but remain ...

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