Lecture C8 + C11 Flashcards
3 functions of bone
-solid support for body, protects vital organs
-bone marrow is site of blood cell production
0reservoir of calcium phosphate and other ions
3 cells of bone
-osteoblats
-osteocytes
-osteoclasts
osteoblasts do what?
-secrete matrix that hardens by calcification, trapping the osteocytes
osteoblats arise from _____
-osteogenic cells
osteocytes do what?
maintain the calcified matrix and receive nutrients from microvasculature
osteoclasts are _____ and do what?
monocytes-derived giant multinucleated cells involved in removing calcified bone matrix and remodelling bone tissue.
osteoblasts? osteoclasts?
-build (bone markers)
-chew (bone breakers)
osteoblasts come from ______. osteoclasts come from _____. osteocytes also can come from ______
-mesenchymal stem cells
-hematopoietic stem cells
-mesenchymal stem cells
Osteoclasts are large multinucleated cells that are derived by the fusion in bone of _______
-several blood-derived monocytes
Osteoclasts are continually ______ while osteoblasts are continually _______. The ongoing balance between osteoblasts and osteoclasts is responsible for the constant but subtle _____
-breaking down old bone
-forming new bone
-reshaping of bone
Osteoblasts are activated by _____ produce ________ and other factors that regulate the formation and activity of osteoclasts.
-parathyroid hormone
-macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor κB ligand (RANKL)
Osteoclasts: M-CSF is required for ______ while ______ itself is controlled by RANKL.
-precursor cell survival
-differentiation
Osteoclast progenitors, express ____, the receptor for M-CSF. Upon M-CSF binding to the receptor, these cells express ______, which is activated by RANKL.
-cFMS
-RANK receptor
Binding of RANKL to RANK, in cooperation with other signals, induce ______. Osteoclast precursors fuse to form ______. Continuous signaling by RANK induces their _____
-differentiation of the progenitor cells to osteoclast precursors.
-multinucleated osteoclasts
-activation to mature, bone resorbing osteoclasts
RANK-RANKL signaling results in a _____. Chemotaxis brings cells towards each other, which is mediated by ______. Cell–cell adhesion is partly mediated by _____, and subsequent cytoskeletal rearrangements are regulated by _____. The ____ cytoskeleton organize to form podosomes, which are ______
-fusion-competent status
- binding of C-C motif chemokine ligand 2 (CCL2) to its receptor (CCR2)
-E-cadherin and integrins
-RAC1
-actin
-specialized macrophage adhesion structures
Podosomes exhibit two distinct features: ________. Podosomes are highly interconnected through a _____. The formation of ____ rings
by podosomes forms the _____.
-an actin core and an adhesive ring complex, containing integrins
and integrin-associated proteins
-dense network of filamentous actin (F-actin).
-actin
-sealing zones
Membrane fusion, and thus the formation of osteoclasts by cell-cell fusion, is mediated by _____
-dendrocyte expressed seven transmembrane protein (DC-STAMP)
Osteoclasts secretes many ____ into the ECM that function in bone remodeling.
enzymes (proteases that digest collagen)
In an active osteoclast, the membrane domain that contacts the bone forms a ____ that binds the cell tightly to the bone matrix and surrounds an area with many surface projections, called _____. This circumferential sealing zone allows the formation of a _____ between the osteoclast and the matrix in which bone resorption occurs.
-circular sealing zone
-the ruffled border
-specialized microenvironment
The sealed space between the osteoclasts and the matrix is _____ by proton pumps. The ruffled border receives _____. Acidification of the sealed space promotes ______ from bone. Together with protein hydrolases that degrades the ECM, this leads to _____. The breakdown products of collagen fibers and other polypeptides are ____ by the osteoclast and further _____, while Ca and other ions are released _____.
-acidified to ~pH 4.5
-secreted matrix metalloproteases and other hydrolytic enzymes
-dissolution of CaPO4 complexes
-localized matrix resorption
-endocytosed
-degraded in lysosomes
-directly and taken up by the blood
Pit- and trench-forming osteoclasts
pit: osteoclasts sits directly on bone
trench: osteoclasts ruffled border on bone surface sideways
trench osteoclast more common in ____. pit?
-men
-women
_____ is released from the bone matrix and activated during osteoclast- mediated bone resorption, ____.
-Transforming growth factor beta (TGF-β1)
-creating a gradient
Synthesis and secretion of TGF-β
(1) TGF-β is synthesized as a precursor protein.
(2) Two TGF-β precursor proteins dimerize through disulfide bridges.
(3) TGF-β-dimer precursor is cleaved by furin to yield the small latent TGF-β complex, that contains latency-associated peptide (LAP) and mature TGF-β peptide connected by noncovalent bonds.
(4) The large latent complex is formed by covalent linking between small latent complex and latent TGF-β binding protein (LTBP), then secreted and incorporated into extracellular matrix.
The LTBP (which is covalently linked to ______) is covalently cross-linked to _____. Osteoclasts can generate an acidic environment ideal for the activation of _____ richly deposited in the bone matrix. Osteoclasts can also activate latent TGF-β by _____, leading to the proteolytic cleavage of ____ and enrichment of ____ within the immediate environment of the bone resorption site.
-small latent TGF-β complex
-extracellular matrix, inactivated
-latent TGF-β
-secretion of proteases
-LTBP1
-active TGF-β
Binding of active TGF-β with the _____ leads to the phosphorylation and recruitment of ____ into a heteromeric receptor complexes. The serine/threonine kinase activity of the activated complex phosphorylates _____ that both bind to ___ and translocate into the nucleus to enhance gene transcription by _____
-TGF-β receptor type II
-TGF-β receptor type I
-Smad2 and Smad3
-Smad4
-cooperating with DNA transcription factors
Mesenchymal stem cells (MSCs) are activated by ___. They migrate to bone-resorptive sites and differentiate into ____.
-TGFβ1
-osteoblasts
Bone remodeling sites are coupled with ______
-bone resorption and formation.
Osteoblast progenitors express the transcription factor ______, a key player in the osteogenesis process.
-runt related transcription factor 2 (RUNX2)
Osteoblasts are _____ specialized for the active
secretion of ECM. These cells have a relatively short-lifespan,
estimated at _____.
-polarized cuboidal cells
-3 months in human bones (either die or become osteocytes)
Osteoblasts produce new bone called “____” which is made of bone collagen and other proteins. Then they control _____. Formation of
mineralized ECM results in the _____ that
forms bone.
-osteoid
-calcium and mineral deposition
-hard but lightweight material
Osteocytes are derived from terminally differentiated ______. They are the most abundant cells in bone, composing ____ of all bone
cells in an adult. Once the bone mineralizes, the osteocytes are trapped there and form _____ . Osteocytes can survive throughout _____
-osteoblasts
-90–95%
-an extensive network with each other, with osteoblasts, and with the
lining cells on the bone surface
-the life of an individual
Osteocytes descr.
have a small cell body and show numerous long, dendritic-like cytoplasmic prolongations that form a canalicular system inside bone
During the transition from osteoblasts to osteocytes, the cells extend many _____ which also become surrounded by calcifying matrix
- long dendritic processes
Osteocytes serve as ____ detecting the mechanical load on the bone as well as stress - or fatigue -induced microdamage and to trigger ______
-mechanosensors
-remedial activity in osteoblasts and osteoclasts
Osteoblasts that do not undergo apoptosis or differentiate to
osteocytes become _____.
-bone lining cells
The bone lining cells then play a crucial role bone remodeling by communicating _____ and promoting differentiation of _____
-through gap junctions with osteocytes deep in the bone matrix
-hematopoietic stem cells into osteoclasts.
The bone lining cells are responsible for ______ by removing _____ through the use of _____
-preparing the surface of the bone for remodeling
-nonmineralized collagen fibrils
-matrix metalloproteinases
Duchenne muscular dystrophy (DMD) is what?
genetic disorder characterized by progressive muscle degeneration and weakness.
DMD symptom onset is in ____ and the disease primarily affects ______ because _____
-early childhood between ages 2-3
-boys
-gene affected in on X chr
DMD is caused by mutations in ____ (encoding _____) that prevent the production of the _____.
-DMD gene (largest gene)
-dystrophin
-muscle isoform of dystrophin
DMD gene is located on _____. DMD inheritance pattern? passed on by _____
-X chromosome
-X-linked recessive
-carrier mother (unaffected)
DMD in females?
rare; limited to females with Turner syndrome (X0) -only one X chr
Dystrophin functions in muscle as a ______. Dystrophin is a component of the _____, which anchors the cytoskeleton to the ______ and stabilizes the ______ in response to contractions. Due to the modular structure of the dystrophin protein domains, ______ of dystrophin can retain function.
-mechanical link to tether the actin cytoskeleton to the inner surface of the sarcolemma
-dystrophin-glycoprotein complex (DGC)
-extracellular matrix
-muscle membrane
-internally truncated forms
Dystrophin deficiency results in the disassembly of the ______ and in loss of the interaction between ______.
-dystrophin-glycoprotein complex (DGC)
-F-actin and the extracellular matrix
Antisense oligonucelotides (AON) do what?
-promote exon skipping
-promote exon exclusion
-block translation
Epidermolysis bullosa (EB) is an incurable group of rare genetic diseases characterized by _____ and ______, inducible by minimal trauma.
-mucocutaneous fragility
-blister formation
Patients with EB can be _____; at the extreme end of the phenotypic spectrum, the disease can become ______.
-mildly to severely affected
-disabling or fatal
Treatment of EB is _______; no available treatment can resolve the disease or its manifestations.
-symptomatic
genes implicated in EB
-16 genes encoding proteins influencing cellular integrity and adhesion (laminins, integrins, collagens)
Mammalian skin consists of the _____ and _____, separated by a _______. The comprises ______ that anchor the epidermis to the dermis.
-epidermis
-dermis
-basement membrane
-extracellular matrix macromolecules
_______ of the intracellular cytoskeleton network attach to hemidesmosome plaques on the ______ of keratinocytes. Hemidesmosomes are linked to the underlying _____ via thread-like ______.
-Intermediate filaments
-basal plasma membranes
-lamina densa
-anchoring filaments
______ deficiency causes continuous skin blistering; healed with ____. Patients with mutations in ____, the gene that codes for collagen VII. Herpes simplex virus was engineered to deliver normal ____ genes. The gene therapy was then incorporated into a ____ so it could be applied to the skin.
-LAM5-β3
-skin graft epidermal sheets expressing normal LAM5-β3
-COL7A
-COL7A1
-gel
Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous neurobiological disorder of _______, affecting 5–7% of children worldwide.
ADHD is one of the most common _______ of childhood.
ADHD may occur either as an _______ with other neurological, psychiatric, and neurodevelopmental disorders.
-inattention, impulsivity, and hyperactivity
-neurodevelopmental disorders
-isolated condition or as comorbidity
Dopaminergic neurons are primarily located respectively in the______ and control various functions.
______ contribute to the symptoms of inattention, hyperactivity, and impulsiveness in attention-deficit hyperactivity disorder.
-midbrain
-Anomalies in dopamine levels
The most widely used medications of ADHD are two psychostimulants, ______
methylphenidate (MPH) and the amphetamines (AMP)
methylphenidate (MPH) do what?
binds to NET and DAT, inhibiting the reuptake of norepinephrine and dopamine.
amphetamines (AMP) do what? (3)
- transported by the monoamine transporters DAT and NET, thus competing with those neurotransmitters (dopamine/norepinephrine)
and decreasing their reuptake in the synapse
-cause trace amine-associated receptor 1 (TAAR1) to phosphorylate DAT. The phosphorylated DAT is either internalized into the presynaptic neuron and ceases transport or inverses the efflux of dopamine
-enter the presynaptic vesicle and cause efflux of neurotransmitters off the vesicle, which in turn augments the efflux towards the synapse.
DAT is _____. NET is ____
-dopamine transporter into cells
-norepinephrine transporter
