KERATINOGENEZA

Este functia specifica prin care epidermul produce zilnic 0,6 – 1 gram keratina. Biosinteza
keratinei respecta schema sintezei proteinelor si se desfasoara incepand cu celulele stratului bazal
(keratinoblaste), continuandu-se in celelalte straturi ale epidermului. O ipotetica pierdere a acestei
functii nu ar fi compatibila cu viata.

In celulele bazale se formeaza prekeratina. Se sintetizeaza initial lanturi polipeptidice care

formeaza protofilamente apoi, prin agregare longitudinala formeaza filamente si ulterior
tonofilamente (denumite si filamente intermediare de keratina). La nivelul stratului bazal,
tonofilamentele sunt subtiri (50 Å), marimea lor marindu-se odata cu avansarea keratinocitelor spre
suprafata epidermului. In stratul malpighian, grosimea tonofilamentelor este de 100 Å, iar in stratul
cornos de 400 Å. Concomitent are loc transformarea cisteinei din prokeratina in cistina, care prezinta
legaturi disulfidice (S-S) stabile, ireversibile.

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 In stratul granulor este sintetizata keratohialina, care este liantul fibrelor de keratina. Studii
recenta arata ca in structura keratohialinei intra:

- Profilagrina – este o proteina insolubila, neutra, bogata in serina, glicina, glutamina, histidina
si arginina. In zona de tranzitie granulos/cornos, sufera proccesul de defosforilare si
proteoliza, formanduse filagrina. Filagrina, ca proteina matrice, contribuie la formarea
macrofibrelor de keratina.
- Loricrina – este un polipeptid bogat in glicina, serina, cisteina, cu masa moleculara 26 kDa.

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 In malpighinianul superior apar keratosomii (corpii Odland), considerati ca fiind cea de-a treia
componenta implicata in procesul de keratogeneza.

In urma procesului de keratinizare epidermica, keratinocitele ajunse in stratul cornos au un

invelis celular format prin legaturi ireversibile intre numeroase tipuri de proteine (locrina,
involucrina, keratolinina, polipeptidul de 195 kDa, cornifina), iar in interior macrofibrile de keratina
care ocupa inreaga celula, nucleul si organitele lipsind.

Filamente de keratina in celule epiteliale

Fotografie la microscop cu imunofluorescenta a

unor filamente de keratina (verde) pe o lama cu
celule epiteliale. Filamentele fiecarei celule sunt
conectate indirect cu cele adiacente prin
desmozomi. O a doua proteina (albastru) a fost
marcata pentru a evidentia membranele celulare.

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 Exista mai multe clasificari ale keratinelor:

- Dupa structura spatiala:

 α-keratina, care este keratina stabila
 β-keratina, considerata keratina reversibila.
- Dupa localizare:
 Keratina moale, continuta in epiderm. Are cantitate redusa de sulf si de cistina
 Keratina tare, prezenta in unghii si in corticala firului de par
- Dupa Moll si colaboratorii, exista:
 Keratine tip I (acide) ce cuprind K10 – K20, caracterizate prin masa moleculara de 40-
56,5 kDa, codate de o familie de gene de pe cromozomul 17;
 Keratine de tip II (neutre/bazice) ce cuprind K1 – K9. Acestea au masa moleculara 52
– 67 kDasi sunt codate de o familie de gene de pe cromozomul 12.

Keratinele epiteliale formeaza heterodimeri prin asocierea unei keratine de tip I cu keratina
de tip II, cum ar fi K10/K1, K10/K2, K13/K4, K14/K5, K16/K6. In stratul bazal se sintetizeaza
predominant K1/K5 care se asambleaza in filamente intermediare de keratina. Aceste keratine scad
in stratul spinos si creste sinteza de K1 si K10 care vor forma la randul lor filamente intermediare de
keratina. Cele 20 de keratine despre care am vorbit pana acum sunt keratine epiteliale.

In structura parului si unghiilor intra o

combinatie de keratine epiteliale si
keratine specifice. Keratinele pilare, in
numar de 10, denumite generic
keratine H, apartin celor doua tipuri
(acid – Ha si bazic – Hb). Ele sunt codate
de gene localizate pe cromozomul 17q
12-21 si 12q 13.

Factorii reglatori ai keratinogenezei

- Factorii intrinseci:
 Chalona epidermica este sintetizata de celulele malpighianului superior si are actiune
pe keratinocitele ce poseda receptori specifici. Ea suprima mitozele, actiune ce este
potentata de hormonii de stres (adrenalina, catecolamine) si de glucocorticoizi.
Chalona epidermica este in concentratie mai mica la bolnavii cu psoriazis si in zonele
cu presiune mecanica pe epiderm. S-a derscris un ritm circadian al chalonei
epidermice, cu acrofaza matinala.

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  Factorul de crestere al epidermului (Epidermal Growth Factor) stimuleaza
epidermopoieza, diferentierea celulara si keratinogeneza;
 TGF α (Transforming Growth Factor α) si KGF (Keratinocyte Growth Factor)
stimuleaza epidermopoieza.
 TGF β1 si TGF β2 suprima proliferarea epidermica iar in anumite conditii pot induce
diferentierea epidermica
 Interferonul γ suprima proliferarea epidermica
 Prostaglandinele F si poliaminele stimuleaza epidermopoieza si keratinogeneza

- Factori extrinseci:
 Factorul hormonal: hormonii androgeni stimuleaza epidermopoieza, iar hormonii
tiroidieni o deprima.
 Factorul nervos: la hemiparetici si polinevritici epidermopoieza este redusa in zona
interesata;
 Factorul mecanic creste epidermopoieza si keratinizarea
 Factorul medicamentos – vitamina A, precum si acizii grasi hidroxilati incetinesc
epidermopoieza. De asemenea, vitamina D este un inhibitor puternic al proliferarii
epidermice.

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Major cellular functions of cytoplasmic intermediate filaments.

(a) Mechanical support. The epidermis is a good example to illustrate this function that is shared
by all major types of intermediate filament (see Table 1). Keratin intermediate filaments are
abundant in keratinocytes, ranging from > 10% of total proteins in progenitor basal cells to >
70% in late-differentiating cells. Changes in filament colour reflect differential expression and
composition of keratins in basal, early- and late-differentiating cells (differentiation proceeds
with the arrow). Keratin filament networks extend throughout the entire cytoplasm in
individual keratinocytes and are integrated between cells by attachment at desmosome cell–
cell junctions (red dots) and between basal cells and the basal lamina by attachment at
hemidesmosomes (yellow dots). This organization maximizes the mechanical support
provided by keratin filaments. (b) Cytoarchitecture. In motor neurons, the radial growth of
axonal processes requires their interaction with neurofilaments (light blue) to exhibit correct
stoichiometry between the light (NF-L), medium (NF-M) and heavy (NF-H) subunits (see Table
1). The large C-terminal tail domains of NF-H (red) and NF-M (orange) subunits are
hyperphosphorylated and project away from the filament core, thereby determining
interfilament spacing and axonal calibre. The many neurofilaments interact with the less
frequent microtubules (dark blue) and with subcortical actin filaments (dark green) through
cytoskeletal linker proteins, such as plectin and BPAG1 (yellow). Adapted from reference 32.
A cytoarchitecture role has also been shown for nuclear lamins and other cytoplasmic
intermediate filaments, such as desmin and keratin. (c) Cell migration. In circulation,
lymphocytes resist haemodynamic and mechanical stresses, owing in part to their vimentin
intermediate filament network (see Table 1), which is organized in a cage configuration at
the cytoplasmic periphery (left cell). After chemokine-induced chemotaxis, for example at
sites of active inflammation, vimentin intermediate filaments are rapidly move to the
perinuclear region at the cell uropod. This is made possible partly through the site-specific

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 phosphorylation of vimentin subunits (depicted by a change in filament colour in the cell,
right), and correlates with a softening of the viscoelastic properties of the cytoplasm,
presumably to allow the pliability needed during extravasation. The same general principles
underlie the ability of epithelial cells to migrate into a wound site after injury. (d) Signal
modulation. Cytoplasmic intermediate filaments can bind and modulate the activity of
signalling proteins, thereby influencing the flow of extracellular signals to relevant terminal
effectors inside the cell. Two possible mechanisms are shown. Left, interactions of
intermediate filaments with cell surface receptors, such as Fas, modulate their density and
function; right, regulated interactions between intermediate filaments and an adaptor
protein, such as TRADD (pink), near the cell surface limits the availability of this adaptor to a
ligand-bound receptor that is poised to transmit a signal to the cell. Regulation of either type
of interaction, conveyed here by a local change in filament colour (blue or red), can be
mediated by dynamic post-translation modifications, association with other proteins or local
differences in the composition of intermediate-filament subunits. Both of these mechanisms
may participate in regulating the response of epithelial cells to pro-apoptotic signals and
other signalling events.

A (neutral-basic) B (acidic) Occurrence

keratin 1, keratin 2 keratin 9, keratin 10 stratum corneum, keratinocytes
keratin 3 keratin 12 cornea
keratin 4 keratin 13 stratified epithelium
keratin 5 keratin 14, keratin 15 stratified epithelium
keratin 6 keratin 16, keratin 17 squamous epithelium
keratin 7 keratin 19 ductal epithelia
keratin 8 keratin 18, keratin 20 simple epithelium

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