CSB331H1 Lecture 16: csb331 lecture 16

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University of Toronto St. George
Cell and Systems Biology
Maurice Ringuette

Endochondral Ossification and Blood Vessel Formation - Lecture 16 Formation of cartilage and bone - endochondral bone formation • Scelerotome --> cartilage --> bone ◦ Endochondral ossification: ‣ Bone formed though cartilage intermediate somite and lateral plate derivatives, vertebral columns, ribs ‣ Endochondral ossification is for long bones such as fingers, feet, etc. • Vertabrae, ribs from sclerotic and limb bones from lateral plate mesoderm • Other route for bone formation: Intramembranous ossification ◦ Mesenchymal tissues directly converted to bone ◦ Neural crest derived bone: flat bones of skull Cartilage, bone and dermis are connective tissues: • Chondrogenesis is the first template/skeletone that is made in our body (cartilage) • Surface of skin has to be able to resist mechanical stress and this is largely due to cytokeletal elements • Chondrocytes, osteoblasts, fibroblasts are examples of connective tissue cells ◦ secrete abundant ECM, rich in collagens and reside within their secreted matrix ◦ provide the body's architectural framework and tissue shape ◦ contribute to support and repair ~every tissue and organ Fibroblasts in CT: • Weaving pattern and the matrices are binding a lot of growth factors with matrix remodelling MMPs when tissues are forming disease states, such as cancer. Most of the time we undergo remodelling but its not so rapid that you want to have lots of MMPs in tissue • Other matrix components that fill the gaps with a hydrated gel; glycoproteins, hyaluronan, and proteoglycans, have been enzmatically removed Connective tissue cell types: • Fibroblasts are considered the least specialized connective tissue cells • Fibroblasts reside in CT tissue throughout the body ◦ Secrete fibrillar collagens I and III ◦ In reponse to injury, fibroblasts proliferate, migrate into wound, deposit and contract collagens to promote repair ◦ Solarity lifestyle; easy to grow in culture Interconversions between connective tissue cell types • Not all fibroblasts are equally pluripotent • Bone mesenchymal stem cells (BMSCa) are highly versatile • Dermal fibroblasts are not versatile, but can still show tens-differentiations: e.g. in response to TGFB, alter actin isoform --> alpha smooth muscle actin (aSMA) • If you want to know if a normal fibroblast has been transformed into highly contractile myofibroblast, you would stain the cell with antibody against aSMA • ECM cues: CT cells are surrounded by it • Osteoblasts and chondrocytes secrete matrix and other factors that recruit surrounding cells to differentiate the same way Cartilage and bone are distinct tissues: • Fromation of the skeleton depends on an intamite partnership between them • Cartilage: ◦ Matrix: structurally simple, highly hydrated, deformable, somewhat resistant to compressive forces ◦ Perichondrium is outside the cartilage, without it cartilage becomes damaged ◦ Tissue growth by expansion: cells proliferate and secrete surrounding ECM ◦ Bother collagen II and proteoglycans • Bone: ◦ Tough, covalentyl cross-liniked collagen I fibrils --> tensile strength ◦ Hydroxyapatite crystals (calcium phosphate) --> resist compression ◦ Tissue growth by apposition: deposition of matrix on free surfaces Collagens - the most abundant ECM molecules: • Fibrous proteins, abundant in skin & bone • ~25% of body's protein mass is collagen, mainly collagen I • 3 polypeptide chains wound around each other to form rope-like triple-helix • After secretion, assemble into fibrils • Covalent cross-links are formed within and between chains --> Tensile strength Collagen matrix is composed primarily of col II and the proteoglycan aggrecan: • Proteoglycans: GAG (disaccharide) chains covalentyl linked to a protein core ◦ (-) charged, bind cations and attack water, and from BULKY hydrated gel that resist compressive forces The proteoglycan aggrecan comprises the bulk of the cartilage of the ECM: • Aggrecan aggregates on hyaluron • GAGs are repeating disaccharides that can have thousands of repeats per chain Growth of cartilage tissue by expansion: • Chondrocyte cells proliferate and secrete the ECM that surrounds them • Chondrocytes undergo proliferation and lay down matrix Bone: • You have two types of bone: spongy (trabecular) and compact (cortical) which is mostly in joint region • Bone has a plywood pattern of collagen I fibril organization ◦ Hydroxyapatiie (calcium phosphate) crystals form in gaps between collagen molecules --> which gives combination of tensile strength and resistance to compression • Depostion of bone matrix by apposition: ◦ Some osteoblasts remain free at surface; others become embedded in their own secretions --> osteocytes ◦ Osteoblast are cells that are forming bone and lay down bone matrix. Once that matrix is mineralized and osteoblast gets trapped and it is now called osteocytes ◦ Resident osteocytes occupy a small space- "lacuna" ◦ Communicate with other cells through long cell processes radiating out along passageways- "canaliculi" that form gap junctions ◦ Regulate the activities of cells that remodel the bone matrix • Endochondral bone formation: ◦ Mesenchymal cells begin to undergo condensation and they eventually form cartilage template which will dictate the future shape of the bone. Therefore, the shape of cartilage itself is dictated by the perichondrium ◦ When vasculature and the middle of the long bone where hypertrophic chondrocytes are found. Once the vasculature has come in (once bone osteogenesis begins), you transform perichondrium to periosteum then signalling is occurring so those cells go into the chondrogenic lineage Sox 9 is critical for cartilage formation: • Mice with Sox9 KO in limb bud mesenchymal cells: • Skeletons stained with alcian blue for cartilage and alizarin red for bone • Mutant newborns had very short limbs and cartilage and bone in the mutant limbs were completely absent Hypertrophic chondrocytes surrounding mesencymhal cells --> osteoblasts • Central chondrocytes become hypertrophic and secrete Ihh (Indian hedgehog) • Ihh cuases transcription of Wnt ---> transcription of Runx2 ---> Sox9 off ---> Osteoblast • Runx2 is critical for osteoblast differentiation/bone formation ◦ If you KO runx2 you are le
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