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Connective tissue. Bone Karel Šulc Connective tissue • • • • • 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 • • • • • 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 • • • • 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 • • • • • 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 • • • • • • 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 • • evoked by inflammatory process degenerative state primary inflammation degenerative process • system of locomotion is primarily involved • 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 • • • • • • 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 • • • • • 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 • • • • 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 • • • • • • • 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 • • • • 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 • • • • • • • 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 • • • • • 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 • • • • 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 • • • • • • • 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 • • • • • 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 • inorganic component (60%) – prevalently calcium hydroxyapatite store of 99% of all calcium, 85% of phosphorus, 65% of Na and Mg • organic component proteins in matrix proteins produced by osteoblasts progenitor cells osteoblasts osteroclasts osteocytes • 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 • • • 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 • • • • • • • 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 • • • • • 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 • • • 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 • • • • • 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) • • • • • “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 • • • 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“