BMS2002 Cell Biology of Disease Lecture 11a PDF

BMS2002 Cell Biology of Disease Molecular insights into higher levels of cellular organization Lecture 11a Specialized connective tissue and ECM: cartilage nnective tissues ve reduced cellular content, (cell-cell contact is rare) ith increased extracell...

BMS2002 Cell Biology of Disease Molecular insights into higher levels of cellular organization Lecture 11a Specialized connective tissue and ECM: cartilage nnective tissues ve reduced cellular content, (cell-cell contact is rare) ith increased extracellular matrix (ECM) content, ompared to epithelial, muscle and nervous tissue...therefore, ECM is the main stress-bearing component o onnective tissues and forms an indirect means of ell-cell contact Composition of the extra cellular matrix (ECM): Composition of the ECM: The ECM is a network of fibrous proteins and hydrated proteoglycans which surround cells in tissues The ECM: strengthens and supports tissues guides cell migration and polarity transports nutrients and waste permits intercellular communication Maintenance of a healthy ECM depends on the balance between synthesis and breakdown of matrix i.e. ECM is not an inert framework components Cartilage: a specialized connective tissue main types: hyaline: ribs, nose, larynx, trachea, articular joints fibro: joint capsules, ligaments elastic: ear, epiglottis, larynx Cartilage: a specialized connective tissue main types: hyaline: ribs, nose, larynx, trachea, articular joints (pre-cursor for bone) fibro: joint capsules, ligaments (least flexible, fewest cells, highest collagen) elastic: ear, epiglottis, larynx (most flexible due to bone increased (femur) elastin, most cells) articular cartilage bone (fibula) bone (tibia) http://www.londonkneeclinic.com Cartilage: a specialized connective tissue e.g. hyaline: ribs, nose, larynx, trachea, articular joints defined by the presence of the indigenous chondrocyte Collagen (type II) and aggrecan are the two key components found in articular cartilage which are especially important for strength and support Loss of collagen integrity leads to loss of strength of matrix Collagen biosynthesis Ehlers Danlos syndrome defective deposition of collagen – hyperextensible joints Diseases caused by mutations in collagen genes or collagen processing enzymes Gene Disease COL1A1;COL1A2 OI, EDS (EHLERS-DANLOS SYNDROME) types I, II, VIIA and VIIB, osteoporosis COL2A1 Several chondrodysplasias § COL3A1 EDS type IV, arterial aneurysms COL4A3;COL4A4;C Alport syndrome OL4A5 COL4A5; COL4A6 Alport syndrome with diffuse oesophageal leiomyomatosis COL5A1; COL5A2 EDS types I and II COL6A1; COL6A2; Bethlem myopathy COL6A3 COL7A1 EB, dystrophic forms COL8A2 Some forms of corneal endothelial dystrophy COL9A1; COL9A2; Multiple epiphyseal dysplasia, intervertebral disc disease, COL9A3 osteoarthritis COL10A1 Schmid metaphyseal dysplasia COL11A1; Several mild chondrodysplasias §, non-syndromic hearing COL11A2 loss, osteoarthritis COL17A1 Generalized atrophic benign EB COL18A1 Knobloch syndrome Lysyl hydroxylase 1 EDS type VI Procollagen N- EDS type VIIC proteinase Aggrecan (complex PG) (high MW GAG) (low MW GAG) (low MW GAG) PG are highly charged (due to GAG content) and therefore attract water and form a hydrated gel: which provides resistance to compression results in swelling pressure (turgor) provides strength and support The presence of PG in cartilage is essential Adult cartilage only contains one cell type: the chondrocyte only 5-10% of ECM volume large and mature, in groups of 2-8 cells rich in RER and Golgi secrete high amounts of type II collagen and aggrecan this ECM were chondrocytes are fou avascular (hypoxic) alymphatic aneuronal Chondrocytes are highly specialized indigenous cells…… …….that differentiate during embryonic development from MSC to secrete components that establish the ECM that is cartilage Chondrocytes are highly specialized indigenous cells…… …….that differentiate during embryonic development from MSC to secrete components that establish the ECM that is cartilage MSC  MSC that differentiate into chondrocytes have a key transcriptional signature expression of Sox-9 (HMG-box DNA binding transcription factor) leads to Col2A expression ondrocyte proliferation and ECM synthesis requires: Sox-9 TGF-b, fibroblast growth factor (FGF), insulin-like growth factor (IGF-1), and parathyroid hormone-related protein (PTHrP) chondrocytes (cartilage) As a result of “spatial” chondrocyte proliferation and EC synthesis, the “cartilage model” forms during embryonic dev Bone formation: Ossification Intramembranous/Endochondrial Ossification Endochondrial Ossification: “cartilage model” is replaced by bone during fetal development. e.g. long bones initiated by differentiation of MSC into osteoblasts, chondrocytes die and cavities (lacunae) form. Production of cartilage is required for bone formation (ossification) osteoblasts atial patterning (location) of chondrocyt ring bone formation is orchestrated by secreted signaling molecules termed morphogens via inductive signaling ring cartilage/bone formation inductive signaling requires morphogens passing between cells through the developing ECM ring cartilage/bone formation inductive signaling involves members of the Hedgehog family of proteins (discovered in Drosophila: Sonic (SHH), Desert (DHH), Indian IHH) …that controls the production of the key skeletal morphogen PTHrP. IHH and PTHrP interact via positive feedback loops that maintain spatial chondrocyte proliferation ring cartilage/bone formation in Drosophila, secreted Hedgehog, via interaction with Patched and Smoothened, keeps proteolytic processing of Cubitus interruptus (Ci) turned off, so it can move to nucleus and activate gene expression edgehog signaling no hedgehog secreted hedgehog active Smoothened internalized IHH degraded Cant can’t prevent Ci cleavage (Note: Ci = GL11-13 in vertebrates) e.g. PTHrP PTHrP binds to a G-protein coupled receptor (GPCR) leading to +ve feedback inactive G protein/enzyme PTHrP e.g. PTHrP chondrocyte proliferation/lack of differentiation more PTHrP e.g. sox-9/RunX-2 more IHH  Formation of long bones from the cartilage model initiates at primary ossification centres tilage is catabolized and osteoid ECM (contains hydroxyapa and collagen) becomes calcified, trapping osteoblasts proximal epiphysis diaphysis birth distal epiphysis BMS2002 Cluster 3 AK; Lecture 1/5 Cartilage and long bone formation (Endochondral ossification) are tightly linked during development by chondrocytes, osteoblasts and osteocytes cartilage  IHH/PTHrP feedback in long bone formation PTHrP maintains chondrocyte proliferation and cartilage production and prevents (1) their terminal differentiation (although they do become slightly differentiated). As the proliferating cells move further way from the central cells these start to receive less PTHrP Kronenberg 2003 Nature 423, 332- and this also reduces IHH and so they make less atial patterning (location) of chondrocyte ring bone formation IHH, PTHrP IHH, PTHrP IHH, PTHrP less PTHrP less proliferation/more differentiation/death IHH, PTHrP proliferating chondrocytes IHH, PTHrP IHH, PTHrP  Key features of articular cartilage connective tissue ECM that directs bone development during embryogenesis essential for permitting mechanical load and movement of articulated bones contains a single cell type – chondrocyte  Quiz/coffee time List the key features of the chondrocyte that allow it to fulfill it’s specialized role Describe the process of inductive signaling How does the morphogen IHH induce hyaline cartilage polarization within the long bones