Transcriptional regulation of bone marrow thrombopoietin by platelet proteins

Abstract

Platelet production is regulated primarily by the cytokine thrombopoietin (TPO). Although TPO is expressed in several different tissues, only in the bone marrow has the level of expression been reported to increase in response to reduced numbers of platelets. In these studies we demonstrate that platelet granule proteins are able to transcriptionally repress TPO mRNA expression in a marrow stromal cell line as well as in primary bone marrow stromal cell cultures. Like TPO mRNA, secretion of TPO protein was also suppressed by serum treatment. Reporter gene constructs indicate that DNA elements located in an approximately 1.9 kb region between 250bp upstream of the transcriptional initiation site and the middle of the second intron are able to mediate the transcriptional repression.

Increased Differentiation of Dermal Mast Cells in Mice Lacking the Mpl Gene

“…If stimulated with TPO again, the stem cell progeny enters into quiescence, returns to the osteoblast niche, and retain stemcellness [26,56]. In contrast to the constitutive TPO expression of the liver, expression of TPO in the marrow is exquisitely regulated by the platelets that establish a negative regulatory loop on the ability of the osteoblasts to produce TPO [25]. In addition, the granules within the platelets contain both factors that stimulate (platelet-derived growth factor [PDGF] and fi broblast growth factor 2 [FGF2]) and those that inhibit (platelet factor 4, thrombospondin, and TGF-β) TPO production by the stromal cells of the medulla [58].…”

“…This would suggest that TPO, a growth factor produced by the osteoblasts [25] and present in the marrow stem cell niche [26], might be involved in the regulation of mast cell differentiation. Wild-type serosal murine mast cells have been shown in previous work to express the mRNA for Mpl, the receptor for TPO [20], and in vivo mouse treatment with TPO or addition of this growth factor to bone marrow-derived murine mast cell cultures strongly decrease the generation of mature mast cells by inducing apoptosis [27].…”

“…It is currently accepted that TPO is mainly produced in the liver [34] and to a less extent in the bone marrow [25]. Recent evidences indicate, however, that TPO is expressed in a variety of other organs [35].…”

“…For this reason, we investigated the levels of TPO expressed in organs (stomach, intestine, spleen, and ear) rich in mast cells using quantitative RT-PCR and ELISA. As platelets exert multiple controls on the levels of TPO levels expressed in vivo [25,[34][35][36], the amount of TPO expressed by tissues of mice in which the number of platelets has been reduced either by bleeding (as a model of acute thrombocytopenia) or by the Mpl null mutation (a model of chronic thrombocytopenia) is also compared. The levels of TPO expressed by bone marrow and liver cells of the thrombocytopenic animals, as well as the levels of TPO protein present in plasma, is presented for comparison.…”

Regulating billions of blood platelets: glycans and beyond

“…43 Further, a number of inflammatory states (eg, ulcerative colitis, rheumatoid arthritis, and ovarian cancer) are associated with increased blood TPO levels and thrombocytosis. 1,38,[44][45][46][47][48][49][50][51] This inflammation-induced increase in TPO expression is mediated by IL-6, which stimulates hepatic TPO messenger RNA (mRNA) expression and production both in hepatocytes in vivo and in hepatoma HepG2 and Hep3B cells in vitro. 49,50,52,53 If hepatic TPO regulation by IL-6 is now well characterized, the ligand-receptor pair regulating hepatic TPO production at steady state has remained elusive.…”