Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 83

BMP6 forms a complex with BMP receptors (BMPR1a, BMPR1b, and BMPR2)
and coreceptor hemojuvelin 52 (Hjv) to activate SMADs. Phosphorylated SMAD1,
SMAD5, and SMAD8 complex with SMAD4 and translocates to the nucleus to
activate HAMP gene promoter. Disruption of the Bmp6 gene in mice reduces
hepcidin synthesis and rapidly causes a massive accumulation of iron in the liver, 53
exocrine pancreas (acinar cells), heart, and renal convoluted tubules [ 153 ].
Hypoxia-inducible factors HIF1 and HIF2 bind to hepcidin HAMP gene pro-
moter and block hepcidin expression. Inflammatory cytokines such as interleukin-6
activate signal transducer and activator of transcription STAT3 that also binds to
HAMP gene promoter and in the presence of SMAD4 induces hepcidin expression.
Erythroid precursors secrete growth differentiation factor GDF15. This cytokine,
a member of the transforming growth factor- β family, may inhibit hepcidin gene

transcription.
Known genetic defects of iron transport and metabolism involve proteins that act
as: (1) iron transporters and exporters such as ferroportin; (2) receptors for iron-
binding proteins, such as transferrin receptor and hemochromatosis; (3) regulators
of iron transporters or iron-binding protein receptors such as hepcidin; and (4) and
regulators of iron metabolism such as transcription factor SpiC that controls
development of red pulp macrophages that recycle senescent RBC products.

3.6 Platelets

Platelets, or thrombocytes (TC), 54

m) anucleate cellular
fragments produced by megakaryocytes . The average lifetime is 10 days. 55

are small (size 2-4

The

10 3 /mm 3 . Platelets circulate in blood to usual concentration is equal to 250-500 ×

ensure hemostasis and wound repair.

complex with the common mediator SMAD4. The resulting complex translocates to the nucleus,
where it primes transcription of target genes.
52 Hemojuvelin (a.k.a. RGMc) belongs to the repulsive guidance molecules (RGM) family.
Members of the RGM family act as coreceptors for bone morphogenetic proteins [ 154 ]. Unlike
other RGM family members (RGMa and RGMb) that are involved in axon guidance in the
central nervous system, hemojuvelin is highly expressed in the liver, skeletal muscles, and heart.
Hemojuvelin synthesized by hepatocytes and myocytes is cleaved from the cell surface to release
a soluble form. Soluble hemojuvelin (Hjv S ) binds bone morphogenetic proteins and operates as a
competitive antagonist of plasmalemmal hemojuvelin, thereby decreasing hepcidin expression.
53 Despite iron overload, hepatocytes of Bmp6-deficient mice have low levels of phosphorylated
Smad1, Smad5, and Smad8.
54

: cell.
55 The life duration of platelets is determined by the interplay between prosurvival BCLxL of the
BCL2 family and the pro-apoptotic BAK, a target of BCLxL in the apoptotic pathway [ 155 ].
Platelets can survive for days. When BCLxL degrades, aged platelets are destined to die. The
balance between BCLxL and BAK thus constitutes a molecular clock for platelet life, BCLxL
maintaining platelet survival by restraining BAK.

θρ o β o ς : clot; κυτ o ς