Environmental PPAR-gamma agonists accelerate aging of bone and impair lymphopoiesis
Baker, Amelia Rachel Haas
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A growing number of environmental contaminants, including phthalates and organotins, are being recognized for their ability to activate peroxisome proliferator-activated receptor γ (PPARγ) and promote adipogenesis, and have been termed environmental obesogens. Organotins have been pollutants of concern in the marine environment due to use as antifoulants; however, organotin use in wood preservatives, plastics manufacturing, and agricultural pesticides has caused widespread environmental contamination. Tributyltin (TBT) is a highly potent activator of PPARγ, as well as its dimerization partner RXR. Bone marrow (BM) is a multifunctional organ which supports bone homeostasis, lymphopoiesis and whole body energy homeostasis. BM multipotent mesenchymal stromal cells (BM-MSCs) differentiate into adipocytes and osteoblasts, the balance of which constitutes the BM microenvironment. PPARγ sits at the crossroad, promoting adipogenesis and suppressing osteogenesis. Osteoblasts are necessary for optimal lymphopoiesis and adipocytes negatively regulate lymphopoiesis. With age, increased marrow adiposity is associated with concomitant loss of osteoblasts, and reduced cellular and humoral immunity. We tested the hypothesis that TBT skews the BM microenvironment, increasing marrow adiposity and suppressing osteoblast differentiation, ultimately impacting both bone quality and lymphopoiesis, a process resembling premature bone aging. TBT induced adipogenesis in a BM-MSC cell line in a PPARγ-dependent manner and also activated liver X receptor (LXR)-dependent gene transcription. TBT concomitantly induced adipogenesis and suppressed osteogenesis in an ex vivo BM-MSC model and increased marrow adipogenesis and reduced cortical bone in vivo. These changes in differentiation were accompanied by PPARγ upregulation and Runx2 downregulation. Surprisingly, shRNA-mediated knockdown of PPARγ revealed its potential role in early osteogenesis. Experiments in ex vivo cultures also revealed that TBT modifies BM-MSC differentiation distinctly from either a PPARγ or an RXR agonist; a likely mechanism, activation of LXR also was evident in vivo. At environmentally relevant concentrations, TBT directly induced apoptosis in developing B cells in vitro and suppressed developing and peripheral B cells in vivo, likely in part by altering the microenvironment in which they mature. Collectively, these studies contribute to the understanding of how environmental contaminants alter the adipocyte-osteoblast balance, contributing new mechanism-based information on how exogenous exposures affect the interrelationship between lymphopoiesis and the BM microenvironment.
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