Transcript Connective tissue. Bone

Connective tissue. Bone
Karel Šulc
Connective tissue
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functions: cell growth, cell differentiation, cell communication with
extracellular matrix
retention of water (maintenance of tissue turgor)
retention of minerals in the bone
„store“ of many cytokines controlling cell proliferation
disturbances of the connective tissue
disturbances of
morphogenesis, creation of the tumor metastases, disturbances of wound
healing
composition of extracellular matrix
fibrous structural proteins (collagen, elastin)
adhesive glycoproteins (fibronectin, laminin)
gel (proteoglycans, salts of hyaluronid acid)
these macromolecules co-creates basal membranes (products of epithelium
+ mesenchymal cells) composition: non-fibrillar collagen (IV), laminin,
proteoglycans
Cells of connective tissue. Matrix
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fibroblasts
standing production of collagen, amorphous matrix
in some tisues
chondrocytes, osteoblasts-osteocytes, synoviocytes
macrophages (antigen present cells)
participation in immune reactions,
synthesis and release of the cytokines, phagocytosis
mast cells, lymphocytes, plasmacells
immune response
reticular cells
synthesis of the reticular fibres; phagocytosis
matrix
free suspension of petides and proteins, lipids, mucoproteins,
glycoproteins, mucopolysacharides
acid mucopolysacharides (glycoseaminoglycans)
bound of water
Connective fibres
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collagen
triple helix of polypeptide chains α1, α2, α3
α-chains
synthesis in ribosomes
postribosomal processing
hydroxylation of proline and lysine remnants; thus high amount of
hydroxyproline and hydroxylysine in the molecule
vitamin C is need to the hydroxylation (it is also need to wound healing)
after hydroxylation of the chains, triple helix is created; fibrills are created
due to influence of pro-collagene peptidase; rise of the collagen is qualified
by rising of cross-linked bounds among chains
defect both in synthesis and structure of the collagene
Ehlers-Danlos
syndrome
Connective fibres
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elastic fibres (elastin, fibrillin)
importance in function of some tissues (vessels, lung, derma, uterus etc.)
stretching force
collagen fibres, original size of tissue is realized by
elastic fibres)
fibroblasts + myocytes
production of elastic fibres
content: great amount of proline, lysine, no hydroxyproline, hydroxylyzine
composition: core (elastin, mw. 70kD) surrounded with net of microfibrils
(glycoprotein fibrillin, mw. 350 kD)
mutation of fibrillin gene
synthesis of abnormal elastic fibres
Marfan syndrome
Influence of some hormons in connective tissue
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glucocorticoids
inhibition of the acid mucoprotein synthesis
disturbance of collagene fibres and matrix synthesis (proteocatabolism)
(Cushing syndrome, overdose of the glucocorticoids
enhanced
vessel fragility, loss of derma elasticity, prolonged wound healing
hypothyroidism
high content of mucopolysacharides and
hyaluronic acid (bound of water) in subcutaneous tissue (myxoedema)
hyperthyroidism
decrease in amount of acid mucopolysacharides
GH
stimulation of the connective tissue, thickening of derma and
subcutaneous tissue, creation of hypertrophic scars
estrogenes
synthesis of mucopolysacharides is stimulated
progesterone
inhibition of MPS synthesis
disturbances of the connective tissue
response to injury
wound healing and its disturbance
reaction of connective tissue is affected by
nutrition
endocrine system function
aging
deficiency of the proteins
deceleration of wound healing,
restriction of the connective tissue resistivity against tensile loading
deficiency of ascorbic acid
disturbance of collagene fibre function due to
lack of hydroxyproline and hydroxylysine in
collagene chains
Diseases of the connective tissue
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evoked by inflammatory process
degenerative state
primary inflammation
degenerative process
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system of locomotion is primarily involved
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synovitis (inflammation of the articular cavity)
acute form
exudative inflammation
fluid retention in the capsule + great amount of PMNC
dilation of vessels
acute form
chronic form (proliferation phase)
Marfan syndrome
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disorder of the connective tissue, manifested principally by changes in the skeleton,
eyes, cardiovascular system
pathogenesis
inherited defect in an extracellular glycoprotein – fibrillin. It is major component of
microfibrils found in the extracellular matrix in organism, abundant in aorta, ligaments,
ciliary zonules of the lens
genes FBN1 and FBN2 encode fibrillin1 and fibrillin2
mutation of FBN1 – Marfan syndrom, mutation of FBN2 – inherited arachnodactylia.
Mutant fibrillin1 disrupts the assembly of normal microfibrills.
skeletal abnormalities: patient is unusualy tall with exceptionally long extremities and
fingers, the joint ligaments are extremelly lax (e.g. thumb can be hyperextended back
to the wrist). Variety of spinal deformities (kyphosis, scoliosis)
eye – bilateral subluxation or dislocation of the lens (ectopia lentis)
cardiovascular system – life-threatening complications: progressive dilation of aortal
valve ring, dilation of the ascending aorta due to medionecrosis, intramural
hematoma (aneurysma dissecans) in 30 – 40% cause of death (rupture of ao. wall)
Ehlers-Danlos syndroms
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genetically and clinically heterogeneous group of disorders
base: defect in synthesis and structure of collagene
tissues rich in collagene are frequently involved – skin, ligaments, joints
skin is hyperextensible and fragile, joints are hypermobile
the basic defect in collagen synthesis and structure may lead to serious
internal complications: rupture of the colon and large arteries, ocular fragility
with rupture of cornea, diaphragmatic hernias
biochemical and molecular base is known only in few forms of EDS – e.g.
mutation of the gene encoding lysyl-hydroxylase (hydroxylysine is
necessary for crossing of the collagen fibrills)
synthesis of the
collagen with disturbed structural stability
Lupus erythematosus
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multiorgan disorder – joints, skin, lungs, kidneys, CNS
onset 20 – 30, acute state, later chronic state
♀ 9 : ♂1
etiology – unknown
genetic predisposition + sex hormone influence
UV radiation, D-penicillamin, hydralazine, procainamid
viral infection – EBV, cytomegaloviruses
pathogenesis – autoantibodies against nuclear antigenes (DNA, RNA,
histones, non-histone proteins bounded to RNA
Lupus erythematosus
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joints – non-erosive synovitis
skin – cell destruction in stratum basale, oedema in dermis, vasculitis,
vascular necrosis
kidneys – various forms of glomerulonephritis (deposition of complexes
DNA-antiDNA, RNA-antiRNA in basal membranes of glomeruli)
cardiovascular system – pericarditis, endocarditis, atherosclerosis
lungs – bronchitis, pleuritis
area v. portae – vasculitis
CNS – vasculitis, focal neurologic signs
Joints and cartilages
Osteoarthritis
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chronic disorder without systemic component
characterization
progressive erosion of articular cartilage
focal loss of cartilage, following hypertrophy of the adjacent bone and
cartilage (creation of osteophytes)
joints of upper and lower limbs are involved (knee-hand disease)
etiology:
trauma – common cause of monoarticular disorder
aging – age related changes in cartilage include alteration in proteoglycans
and collagene
obesity – metabolic changes in cartilage in the course of obesity are
hallmark
genetic factors – polygenic typ of heredity
Osteoarthritis
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disturbance of the articular cartilage – thickness (water, extracelular matrix)
chondrocyte proliferation – reparation is evident
consequently attenuation of hyaline cartilage
enhanced bone remodeling and bone hypertrophy (main sign of OA) –
destruction of the bone surface
enhanced proliferation of osteoblasts
new formation of the bone is not
in concordance with neoangiogenesis
source of bone necrosis
osteophytes
disturbance of the joint surface and articular motion
Clinically:
articular pain, progressive loss of function
Osteoarthrosis
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heterogenous group of diseases – morphological base in all is uniform
multifactorial disease
etiology: genetic predisposition
aging
mechanical influences – joint geometry, capsule flowing
endocrine factors – diabetes mellitus, acromegaly
immune disturbaces – deposition of immunocomplexes in cartilages,
autoantibody creation
proces is started by biochemical changes in cartilages – loss of
proteoglycans; in chondrocytes change in colagene synthesis
loss of cartilage resistivity; bone sclerotization, cysts, osteophytes
clinically: articular pain (free nerve endings in synovia, in periosteum are
stimulated) (cartilage does not content nociceptors), progressive loss of
function
Rheumatoid arthritis
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chronic, systemic inflammatory disease; autoimmune disorder
joints, myocardium, vessels, muscles are involved, esp. joints - proliferative
synovitis, articular cartilage destruction, progressive articular immobilization
1% in population, frequention of disorder during aging is greater
onset in all age groups, in all races and social groups
charakteristics: rheumatoid nodules (central zone of fibrinoid necrosis
surrounded by a prominent rim of fibroblasts, epitheloid histiocytes,
lymphocytes, plasma cells)
localization: skin; lungs, spleen, pericardium, myocardium, heart valves,
aorta, etc.
hallmark of diagnosis: estimation of rheumatoid factor (RF) in blood
autoantibody against Fc fragment of IgG (it is also IgA or IgM in character)
Rheumatoid arthritis - pathogenesis
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RA is triggered by exposure of an immunogenetically susceptible host to an
arthritogenic microbial antigens
initiation of acute arthritis by continuing autoimmune reaction
activation of CD4+
helper T-cells; local release of inflammatory mediators and cytokines
destruction
of the joints
the first step requires
susceptible host – most patients are HLA-DR4 and/or HLA-DR1 positive
microbial/viral antigen – EBV, retroviruses, parvoviruses; Borrelia, Mycoplasma
normal lymphocyte function: antigen present cells
stimulation CD4+
(the amount of CD8+ decreases)
B-lymfo stimulation
RF release
neoangiogenesis – consequence of cytokine release from macrophages – a/b FGF
induction of endothelial cells to invasion into articular cavity and to creation of
capillaries – joint destruction
RF (character IgM) bounds complement
release of mediators from mast cells
microthrombi creation
Rheumatoid arthritis
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proliferative, destructive synovitis; great amount of PMNC in synovia
(release of adhesive molecules from endothelial cells + C5a, leucotrien B4,
PAF
migration of PMNC into articular cavity
PMNC (after phagocytosis of IC) – release of proteinases, collagenases,
elastases
collagene destruction
IL-1, TNFα
acute phase protein synthesis
immunocomplexes
start of coagulative cascade
fibrin
joint destruction
bradykinin (involved tissue), histamin (mast cells), serotonin (thrombocytes)
increase of vessel permeability
diagnosis: morning stifting, arthritis in three or more joint areas, symmetric
arthritis, rheumatoid nodules, serum rheumatoid factor, radiographic
changes (joint effusion, juxtaarticular osteopenia, narrowing of the joint
space, loss of articular cartilage)
Bone
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inorganic component (60%) – prevalently calcium hydroxyapatite
store of 99% of all calcium, 85% of phosphorus, 65% of Na and Mg
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organic component
proteins in matrix
proteins produced by osteoblasts
progenitor cells
osteoblasts
osteroclasts
osteocytes
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cell restoration and activation is controlled by a/b FGF, PDGF, IGF-1, TGFβ
progenitor cells (osteoprogenitor cells)
pluripotent mesenchymal stem cells
osteoblasts
osteoblasts - bone surface
function: creation of new bone (synthesis and release of proteins necessary to
formation of bone matrix an bone mineralization)
receptors for PTH, PTHrP, vitamin D3, estrogenes, cytokines
osteoblasts
osteocytes
osteocytes – reciprocal communication by net of canalliculi
transfer of
membrane potentials, substrates control local Ca and P concentration
osteoclasts – derived from CFU-GM (tissue macrophages)
differentiation of osteoclasts is realized by influenced of IL-1, IL-3, IL-11, TNF,
GM-CSF, M-CSF
during growth
bone modeling (prevalently due to action of osteoblasts
after cartilage closure
remodeling (synchronous action of osteoblasts
and osteoclasts)
primary bone resorption stimulators effect on osteoblast receptors; osteoblasts
release proteins activating osteoclasts
Control of bone metabolism
• PTH, vitamin D3, calcitonin
• PTH – if decline of blood Ca level
increasing of synthesis and
release
evokes mobilization of Ca from bone, increases osteoclasts
activity;
in the kidney – greater resorption of Ca
creation of 1,25 (OH)2 vitamin D3
• vitamin D3 – food intake, synthesis in the skin after UV irradiation
25-OH vit. D3
osteoid mineralization
24,25 (OH)2 vit. D3
osteoblast stimulation
1,25 (OH)2 vit. D3
intestinal Ca resorption, osteoblast
stimulation
• calcitonin, PTHrP (source: thyroid parafollicular cells)
lowering of Ca level in hypercalcemia; osteoblast inhibition
Disturbances of bone tissue
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inherited malformations
non-development of some of fingers, ribs etc.
creation of superabundant fingers, ribs; syndactilia, arachnodactylia
majority of inherited malformations
gene mutation in homeobox
HOX D
disturbance of transcriptional factors
achondroplasia (disease of growth cartilage)
base: mutation of gene encoding FGFR3
clinical: normal lenght of torso, head enlargement, shortening of limbs
intelligence, reproductive efficiency are normal
Osteoporosis
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atrophy of the bone – equal decrease both inorganic and organic part of
bone – normal decrease of bone tissue after puberty = 0,5% / year
etiologic factors
age – progenitor cells
reduction of the proliferative ability, decrease
of osteoblasts -- senile osteoporosis
reduced physical activity
mechanical forces are important stimuli for
normal bone remodeling
importance in long term laying patients
calcium nutritional state – a) decreased intake, b) low resorbtion, c)
increased loss (kidney)
hormonal influences – low production of estrogenes, higher production of
glucocorticoids (decreased production of estrogenes
release of IL-1,
IL-6, TNFα
indirect stimulation of osteoclasts (posmenopausal
osteoporosis)
clinical: isolated or multiple fractures, deformity (spine)
Rickets and osteomalacia
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characterization: defect in matrix mineralization due to lack of vitamin D3 or
some disturbance in its metabolism
in children – rachitis
in adults – osteomalacia
defect in mineralization of osteoid
lack of vitamine
hypocalcemia
release of PTH
mobilization of Ca from bone
in rachitis – deformities, in osteomalacia – fractures
considerably high production of PTH
microfractures, bone cysts,
hemorhage in bones (brown colour of bones and surrounding connective
tissue – deposition of hemosiderin)
osteitis fibrosa cystica
(Recklinghausen´s disease
Rachitis
Osteogenesis imperfecta
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disturbance of α1 or α2 chain of collagene (type I)
bones, joints, eyes, ears, skin, teeth are affected (structures rich in type I
collagen)
shortening of α1 chain – blue sclerae, hearing loss, outstanding bone fragility
death in utero or within days of birth
α2 chain – outstanding bone fragility, blue sclerae, dental
imperfection
in all forms of osteogenesis imperfecta
too little bone
Osteopetrosis
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disease caused by osteoclasts dysfunction
disturbance of bone remodeling, difuse bone sclerotization
thickenig of bone, narrowed of BM cavity
pathogenesis
1) carbonic anhydrase deficiency (lack of H+ needed for solubilization
of bone matrix)
2) osteoclast cannot generate superoxid
cause: mutation of gene encoding M-CSF
clinical signs:
malignant autosomal recessive form: fractures, anemia, hydrocephaly
pospartum mortality – in surviving: cranial nerve problems, extramedullar
hemopoiesis
benign autosomal dominant form: repeated (micro)fractures, mild anemia,
mild cranial nerve problems)
Osteopetrosis
Paget disease (osteitis deformans)
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“collage of matrix madness“
repetitive and overlapping sequence of
1) initial osteolytic state (outstanding activity of osteoclast)
2) mixed osteoclastic-osteoblastic stage – at the end is predominance of
osteoblastic activity
3) burn-out quiescent osteosclerosis
these stages are evident in the bone
cause:
slow virus infection (paramyxovirus)
osteoclast, CFU-GM, MNC
infection
synthesis and release of IL-6 (it is produced by osteoblasts
powerful stimulation of osteoclasts)
clinical signs: one or more bones may be involved. Thickening of bone esp.
of cortex, decrease of bone marrow cavity.
pain
bone overgrowth in the cranofacial skeleton
leontiasis ossea
Renal osteodystrophy
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term renal osteodystrophy describes all of skeletal changes in chronic renal
disease:
increased osteoclastic bone resorption
delayed matrix mineralization
osteosclerosis
growth retardation
osteoporosis
pathogenesis
hyperphosphatemia
secondary hyperparathyroidism
induction
of osteoclastic activity
hypocalcemia due to low production of 1,25(OH)2 vit. D3
PTH
induction of osteoclastic activity
metabolic acidosis
release of calcium from the matrix
clinical signs: osteomalacia (mimicking osteitis fibrosa cystica)
osteoporosis; deposition of masses of amyloid in bone (amyloid is formed
from β2-microglobulin – e.g. it is increased after long-term hemodialysis)
Urémie
Renální osteodystrofie
Zvýšená aktivita příšt.
tělísek způsobující
charakteristickou
subperiostální resorpci
Lebka „sůl a pepř“