Estrogen Promotes Early Osteoblast Differentiation and Inhibits Adipocyte Differentiation in Mouse Bone Marrow Stromal Cell Lines that Express Estrogen Receptor (ER) α or β

Abstract

Although cells of the osteoblast lineage express functional ERs, direct effects of estrogen on bone formation remain obscure. In the present study, we have investigated estrogen effects on osteoblastic and adipocytic differentiation from a mouse bone marrow stromal cell line, ST-2, which had been manipulated to overexpress either human ER alpha (ST2ER alpha) or ER beta (ST2ER beta). Treatment with bone morphogenetic protein-2 increased alkaline phosphatase activity as well as the number of Oil Red O-positive adipocytes, indicating that bone morphogenetic protein-2 stimulated both osteoblastic and adipocytic differentiation from these bipotential cells. In both ST2ER alpha and ST2ER beta cells, cotreatment with E2 caused enhancement of alkaline phosphatase activity and suppression of lipid accumulation. These effects were completely reversed by an ER antagonist, ICI182780. Therefore, the estrogen regulation occurred in an ER-specific manner but without ER subtype specificity. Moreover, dose response curves of the opposing effects of estrogen on osteoblastogenesis and adipogenesis formed an apparent mirror image, consistent with a reciprocal regulation of differentiation into the two cell lineages. These results demonstrate that estrogen directly modulates differentiation of bipotential stromal cells into the osteoblast and adipocyte lineages, causing a lineage shift toward the osteoblast. Such effects would lead to direct stimulation of bone formation and thereby contribute to the protective effects of estrogen on bone.

Soluble Factors on Stage to Direct Mesenchymal Stem Cells Fate

“…Estrogens bind their α and/or β receptors and induce MSCs proliferation and osteogenic and chondrogenic differentiation (Rodriguez et al, 2008), through the activation of BMPs/WNT/β-catenin and p38 MAPKs/NF-κB signaling pathways (Gopalakrishnan et al, 2006; Li et al, 2013b; Kim et al, 2015; Cong et al, 2016). Moreover, estrogens induce early osteoblast differentiation and inhibit adipogenesis in mice (Okazaki et al, 2002). Furthermore, they reduce LPL levels, impair adipocyte progression into hypertrophic state, and influence body adipose tissue depots distribution and glucose metabolism (Post et al, 2008).…”

Marrow Fat and the Bone Microenvironment: Developmental, Functional, and Pathological Implications

“…In fact, aromatase expression was found in MSCs, in osteoblasts and osteoblastlike cells 107,109,110,113,114. Studies during MSCs’ differentiation point to the potential importance of local estrogen production and action for osteogenic and adipogenic commitment and as a negative regulator for adipogenesis 107,110,115–117. These observations support the hypothesis of a threshold estradiol level for normal skeletal remodeling, which could be attained by both appropriate endogenous aromatase activity and estrogenic precursors 118,119…”

Deciphering the molecular and physiological connections between obesity and breast cancer

“…In human adipocytes, estradiol-17β upregulates the expression of ERα and ERβ mRNAs to mediate adipose tissue development and metabolism (Dieudonné et al, 2004). In bone marrow stromal cell lines, estrogen inhibited adipocyte differentiation and promoted osteogenesis (Picó et al, 1998;Okazaki et al, 2002). Estrogen activates the ERK and Akt pathways to increase the expression of leptin in placental cells (Gambino et al, 2010).…”