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Editorials
Acknowledgments
This work was supported by grants from the NIH to OAM (R24 DK092759; R01 DK62876), and from the American Diabetes Association to ZL (1-18-PDF-087).
References
1. Cawthorn WP, Scheller EL, Learman BS, et al. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. 2014;20(2):368- 375.
2. Li Z, Hardij J, Bagchi DP, Scheller EL, MacDougald OA. Development, regulation, metabolism and function of bone marrow adipose tissues. Bone. 2018;110:134-140.
cell niches. Science. 2007;318(5854):1296-1299.
7. Nocka K, Majumder S, Chabot B, et al. Expression of c-kit gene
products in known cellular targets of W mutations in normal and W mutant mice--evidence for an impaired c-kit kinase in mutant mice. Genes Dev. 1989;3(6):816-826.
8. Bosbach B, Deshpande S, Rossi F, et al. Imatinib resistance and microcytic erythrocytosis in a KitV558Delta;T669I/+ gatekeeper- mutant mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci U S A. 2012;109(34):E2276-E2283.
9. Song L, Liu M, Ono N, Bringhurst FR, Kronenberg HM, Guo J. Loss of wnt/beta-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes. J Bone Miner Res. 2012;27(11):2344- 2358.
10. Mizoguchi T, Pinho S, Ahmed J, et al. Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev Cell. 2014;29(3):340-349.
11. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regu- late the haematopoietic stem cell niche. Nature. 2003;425(6960):841-
3. Zhou BO, Yu H, Yue R, et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat 846.
Cell Biol. 2017;19(8):891-903.
4. Li Z, Hardij J, Evers SS, et al. G-CSF partially mediates effects of
sleeve gastrectomy on the bone marrow niche. J Clin Invest.
2019;130:2404-2416.
5. Zhang Z, Huang Z, Ong B, Sahu C, Zeng H, Ruan HB. Bone marrow
adipose tissue-derived stem cell factor mediates metabolic regulation
of hematopoiesis. Haematologica. 2019;104(9):1731-1743.
6. Czechowicz A, Kraft D, Weissman IL, Bhattacharya D. Efficient transplantation via antibody-based clearance of hematopoietic stem
New potential players in hepcidin regulation
Maxwell Chappell and Stefano Rivella
12. Visnjic D, Kalajzic Z, Rowe DW, Katavic V, Lorenzo J, Aguila HL. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood. 2004;103(9):3258-3264.
13. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481(7382):457-462.
14. Scheller EL, Khandaker S, Learman BS, et al. Bone marrow adipocytes resist lipolysis and remodeling in response to beta-adren- ergic stimulation. Bone. 2019;118:32-41.
Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Cell and Molecular Biology Graduate Group, University of Pennsylvania, Abramson Research Center, Philadelphia, PA, USA
E-mail: STEFANO RIVELLA - rivellas@email.chop.edu doi:10.3324/haematol.2019.224311
The manuscript by Liu and colleagues, published in this issue of Haematologica, reports the identifica- tion of novel compounds able to increase hepcidin expression in normal mice as well as in animals affected by hemochromatosis and β-thalassemia intermedia (or non-transfusion-dependent thalassemia) (Figure 1A).1
Hepcidin is the master regulator of iron secreted from the liver and acts on ferroportin, a transmembrane pro- tein that functions as an iron exporter.2,3 Once hepcidin binds ferroportin, the complex is rapidly degraded, pre- venting iron egress.2,3 Ferroportin is expressed in many types of cells, including enterocytes and macrophages.2,3 Therefore, the relative abundance of hepcidin in the cir- culation and ferroportin on cell membranes control iron absorption (from enterocytes) and iron recycling (from macrophages).2,3
Hepcidin expression is regulated by iron, inflammation and erythropoiesis.2,3 With regard to iron-mediated control of hepcidin, this is achieved through at least two mecha- nisms. The first senses the amount of intracellular iron in liver sinusoidal endothelial cells and responds by synthesiz- ing BMP6, and other similar ligands, belonging to the TGFβ-like family.2-4 Increased intracellular concentration of iron leads to secretion of BMP6 from these cells.2-4 As a con- sequence, BMP6 binds and activates receptors that trigger phosphorylation of a SMAD complex and stimulate hep- cidin expression in hepatic cells.2-4
The second mechanism senses the iron in circulation by recognizing iron-loaded transferrin molecules.3
Molecules such as HFE, transferrin receptor-2, and others
communicate intracellularly when the transferrin satura-
3
tion levels increase. It has been hypothesized that this
sensing complex potentiates the SMAD complex activat- ed by BMP6.5 Alternatively, or in addition, it has been suggested that this complex acts upon hepcidin expres- sion by decreasing the ERK1/2 pathway.10
Under conditions that require enhanced red cell pro- duction (as a consequence of a transient or chronic ane- mia), hepcidin synthesis is normally suppressed.2 A few factors have been identified that could play a role in this mechanism, such as erythroferrone and platelet-derived growth factor BB.7,8 In particular, erythroferrone is secret- ed by erythroid cells and acts as a trap ligand, limiting the activity of BMP6 and other similar molecules.9
Another player in the regulation of hepcidin is the mol- ecule matriptase-2 (or TMPRSS6).2,3 This molecule pre- vents hepcidin overexpression, which could lead to hypoferremia and anemia.3,10 Although it is unclear which pathways and molecules control TMPRSS6, it has been shown that TMPRSS6 is required for erythropoietin- mediated hepcidin suppression in mice.11,12
In primary forms of hemochromatosis, patients show excessive iron absorption and suffer from iron overload (Figure 1A).7,8 This happens when hepcidin, or other genes that control its expression, are mutated.2,3 In sec- ondary forms of hemochromatosis (as in β-thalassemia), the anemia triggers increased iron absorption, likely by increased expression of erythroferrone and other hypox-
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