Lecture C8 + C11

Question 1

3 functions of bone

Answer 1

-solid support for body, protects vital organs
-bone marrow is site of blood cell production
0reservoir of calcium phosphate and other ions

Question 2

3 cells of bone

Answer 2

-osteoblats
-osteocytes
-osteoclasts

Question 3

osteoblasts do what?

Answer 3

-secrete matrix that hardens by calcification, trapping the osteocytes

Question 4

osteoblats arise from _____

Answer 4

-osteogenic cells

Question 5

osteocytes do what?

Answer 5

maintain the calcified matrix and receive nutrients from microvasculature

Question 6

osteoclasts are _____ and do what?

Answer 6

monocytes-derived giant multinucleated cells involved in removing calcified bone matrix and remodelling bone tissue.

Question 7

osteoblasts? osteoclasts?

Answer 7

-build (bone markers)
-chew (bone breakers)

Question 8

osteoblasts come from ______. osteoclasts come from _____. osteocytes also can come from ______

Answer 8

-mesenchymal stem cells
-hematopoietic stem cells
-mesenchymal stem cells

Question 9

Osteoclasts are large multinucleated cells that are derived by the fusion in bone of _______

Answer 9

-several blood-derived monocytes

Question 10

Osteoclasts are continually ______ while osteoblasts are continually _______. The ongoing balance between osteoblasts and osteoclasts is responsible for the constant but subtle _____

Answer 10

-breaking down old bone
-forming new bone
-reshaping of bone

Question 11

Osteoblasts are activated by _____ produce ________ and other factors that regulate the formation and activity of osteoclasts.

Answer 11

-parathyroid hormone
-macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor κB ligand (RANKL)

Question 12

Osteoclasts: M-CSF is required for ______ while ______ itself is controlled by RANKL.

Answer 12

-precursor cell survival
-differentiation

Question 13

Osteoclast progenitors, express ____, the receptor for M-CSF. Upon M-CSF binding to the receptor, these cells express ______, which is activated by RANKL.

Answer 13

-cFMS
-RANK receptor

Question 14

Binding of RANKL to RANK, in cooperation with other signals, induce ______. Osteoclast precursors fuse to form ______. Continuous signaling by RANK induces their _____

Answer 14

-differentiation of the progenitor cells to osteoclast precursors.
-multinucleated osteoclasts
-activation to mature, bone resorbing osteoclasts

Question 15

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 ______

Answer 15

-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

Question 16

Podosomes exhibit two distinct features: ________. Podosomes are highly interconnected through a _____. The formation of ____ rings
by podosomes forms the _____.

Answer 16

-an actin core and an adhesive ring complex, containing integrins
and integrin-associated proteins
-dense network of filamentous actin (F-actin).
-actin
-sealing zones

Question 17

Membrane fusion, and thus the formation of osteoclasts by cell-cell fusion, is mediated by _____

Answer 17

-dendrocyte expressed seven transmembrane protein (DC-STAMP)

Question 18

Osteoclasts secretes many ____ into the ECM that function in bone remodeling.

Answer 18

enzymes (proteases that digest collagen)

Question 19

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.

Answer 19

-circular sealing zone
-the ruffled border
-specialized microenvironment

Question 20

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 _____.

Answer 20

-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

Question 21

Pit- and trench-forming osteoclasts

Answer 21

pit: osteoclasts sits directly on bone
trench: osteoclasts ruffled border on bone surface sideways

Question 22

trench osteoclast more common in ____. pit?

Answer 22

-men
-women

Question 23

_____ is released from the bone matrix and activated during osteoclast- mediated bone resorption, ____.

Answer 23

-Transforming growth factor beta (TGF-β1)
-creating a gradient

Question 24

Synthesis and secretion of TGF-β

Answer 24

(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.

Question 25

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.

Answer 25

-small latent TGF-β complex -extracellular matrix, inactivated -latent TGF-β -secretion of proteases -LTBP1 -active TGF-β

Question 26

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 _____

Answer 26

-TGF-β receptor type II -TGF-β receptor type I -Smad2 and Smad3 -Smad4 -cooperating with DNA transcription factors

Question 27

Mesenchymal stem cells (MSCs) are activated by ___. They migrate to bone-resorptive sites and differentiate into ____.

Answer 27

-TGFβ1 -osteoblasts

Question 28

Bone remodeling sites are coupled with ______

Answer 28

-bone resorption and formation.

Question 29

Osteoblast progenitors express the transcription factor ______, a key player in the osteogenesis process.

Answer 29

-runt related transcription factor 2 (RUNX2)

Question 30

Osteoblasts are _____ specialized for the active secretion of ECM. These cells have a relatively short-lifespan, estimated at _____.

Answer 30

-polarized cuboidal cells -3 months in human bones (either die or become osteocytes)

Question 31

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.

Answer 31

-osteoid -calcium and mineral deposition -hard but lightweight material

Question 32

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 _____

Answer 32

-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

Question 33

Osteocytes descr.

Answer 33

have a small cell body and show numerous long, dendritic-like cytoplasmic prolongations that form a canalicular system inside bone

Question 34

During the transition from osteoblasts to osteocytes, the cells extend many _____ which also become surrounded by calcifying matrix

Answer 34

- long dendritic processes

Question 35

Osteocytes serve as ____ detecting the mechanical load on the bone as well as stress - or fatigue -induced microdamage and to trigger ______

Answer 35

-mechanosensors -remedial activity in osteoblasts and osteoclasts

Question 36

Osteoblasts that do not undergo apoptosis or differentiate to osteocytes become _____.

Answer 36

-bone lining cells

Question 37

The bone lining cells then play a crucial role bone remodeling by communicating _____ and promoting differentiation of _____

Answer 37

-through gap junctions with osteocytes deep in the bone matrix -hematopoietic stem cells into osteoclasts.

Question 38

The bone lining cells are responsible for ______ by removing _____ through the use of _____

Answer 38

-preparing the surface of the bone for remodeling -nonmineralized collagen fibrils -matrix metalloproteinases

Question 39

Duchenne muscular dystrophy (DMD) is what?

Answer 39

genetic disorder characterized by progressive muscle degeneration and weakness.

Question 40

DMD symptom onset is in ____ and the disease primarily affects ______ because _____

Answer 40

-early childhood between ages 2-3 -boys -gene affected in on X chr

Question 41

DMD is caused by mutations in ____ (encoding _____) that prevent the production of the _____.

Answer 41

-DMD gene (largest gene) -dystrophin -muscle isoform of dystrophin

Question 42

DMD gene is located on _____. DMD inheritance pattern? passed on by _____

Answer 42

-X chromosome -X-linked recessive -carrier mother (unaffected)

Question 43

DMD in females?

Answer 43

rare; limited to females with Turner syndrome (X0) -only one X chr

Question 44

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.

Answer 44

-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

Question 45

Dystrophin deficiency results in the disassembly of the ______ and in loss of the interaction between ______.

Answer 45

-dystrophin-glycoprotein complex (DGC) -F-actin and the extracellular matrix

Question 46

Antisense oligonucelotides (AON) do what?

Answer 46

-promote exon skipping -promote exon exclusion -block translation

Question 47

Epidermolysis bullosa (EB) is an incurable group of rare genetic diseases characterized by _____ and ______, inducible by minimal trauma.

Answer 47

-mucocutaneous fragility -blister formation

Question 48

Patients with EB can be _____; at the extreme end of the phenotypic spectrum, the disease can become ______.

Answer 48

-mildly to severely affected -disabling or fatal

Question 49

Treatment of EB is _______; no available treatment can resolve the disease or its manifestations.

Answer 49

-symptomatic

Question 50

genes implicated in EB

Answer 50

-16 genes encoding proteins influencing cellular integrity and adhesion (laminins, integrins, collagens)

Question 51

Mammalian skin consists of the _____ and _____, separated by a _______. The comprises ______ that anchor the epidermis to the dermis.

Answer 51

-epidermis -dermis -basement membrane -extracellular matrix macromolecules

Question 52

_______ of the intracellular cytoskeleton network attach to hemidesmosome plaques on the ______ of keratinocytes. Hemidesmosomes are linked to the underlying _____ via thread-like ______.

Answer 52

-Intermediate filaments -basal plasma membranes -lamina densa -anchoring filaments

Question 53

______ 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.

Answer 53

-LAM5-β3 -skin graft epidermal sheets expressing normal LAM5-β3 -COL7A -COL7A1 -gel

Question 54

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.

Answer 54

-inattention, impulsivity, and hyperactivity -neurodevelopmental disorders -isolated condition or as comorbidity

Question 55

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.

Answer 55

-midbrain -Anomalies in dopamine levels

Question 56

The most widely used medications of ADHD are two psychostimulants, ______

Answer 56

methylphenidate (MPH) and the amphetamines (AMP)

Question 57

methylphenidate (MPH) do what?

Answer 57

binds to NET and DAT, inhibiting the reuptake of norepinephrine and dopamine.

Question 58

amphetamines (AMP) do what? (3)

Answer 58

- 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.

Question 59

DAT is _____. NET is ____

Answer 59

-dopamine transporter into cells -norepinephrine transporter