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. 2012 Jul 29;5(6):503–511.

Figure 4.

Figure 4

Schematic depicting a central role for transforming growth factor (TGF)-β1 signaling in osteoclastogenesis and immune dysregulation of osteolytic Langerhans cell histiocytosis (LCH). Specifically, TGF-β1 expression [20,25] and signaling in osteolytic LCH correlates with and could lead to:1) interleukin (IL)-11 [20,22,28,32] and in turn, both osteoclastogenesis [21,33] and the activation of signal transducer and activator of transcription (STAT)3 pathway [34], evidenced by nuclear expression of phosphorylated (p)-STAT3 (Tyr 705) and subsequent expansion of the FoxP3 + population via IL-23 [36,37,41]; 2) nuclear expression of glioma-associated oncogene protein (Gli)2 [26,30] leading to the formation of parathyroid hormone-related protein (PTHrP) and then to activation of RANKL with osteoclastogenesis [26,31,46,47]; 3)fatty acid synthase (FASN) expression with lipogenesis to include phosphocholine (choline-phospholipids have been described in LCH [44]) and phosphatidlycholine [45], the substrate for phospholipase (PL)D1 with subsequent phosphatidic acid(PA) and lysophosphatidic acid (LPA) formation and in turn to complex activation of protein kinase C (PKC)-α, PLD1 and TGF-β1 [48-57]; 4) activation of PKC-α [58-60]; and 5) downregulation of CD8+ cell-associated immune surveillance[61] and with activation of T regulatory (FoxP3+) cells [35,38-40]. Targeted therapeutic possibilities in this context include metformin to : 1. Activate AMPK with inhibition of TGF-β{Smad3}-associated Gli2 and IL-11 signaling [26-31,62,63] and in turn, inhibition of PTHrP and RANKL signaling [46,64,65] with reduced osteoclastogenesis; 2. Downregulate FASN [66] leading to reduced substrate for the PLD1/PKC-α/TGF-β signaling axis; and 3. Inhibit STAT3 activation at tyrosine 705 [67]. Moderators of TGF-β pathway signaling related to immune dysregulation include: thalidomide, which has shown efficacy in blocking the TGF-β pathway [16-19] and clinically, in treating osteolytic LCH [15]; and metronomic cyclophosphamide , which targets T regulatory cells [68]. *Indicates protein analytes identified in osteolytic LCH.