Congenital and Developmental Diseases of Bone

Question 1

What are the two components of bone matrix?

Answer 1

osteoid (35%) and inorganic mineral component (65%)

Question 2

What is the predominant collagen type in osteoid? What are the characteristics of it?

Answer 2

type 1 (triple helix composed of two alpha-1 chains and one alpha-2 chain)

Question 3

What are the characteristics of type 1 collagen?

Answer 3

calcium hydroxyapatite

Question 4

What is the role of calcium hydroxyapatite?

Answer 4

gives bone its hardness and also serves as a repository for 99% of the body’s calcium and 85% of its phosphorus (relevant to maintaining homeostasis of the blood levels of these elements).

Question 5

What are the two histologic forms of bone matrix?

Answer 5

woven and lamellar

Question 6

Describe woven bone. When is it made? What does it look like?

Answer 6

Woven bone is rapidly produced during fracture repair, fetal development and various diseases. It has haphazard arrangement of collagen fibers.

Question 7

Is presence of woven bone in adults normal?

Answer 7

NO–always pathologic

Question 8

How does lamellar bone differ from woven bone?

Answer 8

it is slowly produced, with collagen fibers in parallel array, which imparts more structural integrity to it than woven bone

Question 9

What are the 4 cell types in bone?

Answer 9

osteoprogenitor cells, osteoblasts, osteoclasts and osteocytes

Question 10

What is the function of osteoprogenitor cells?

Answer 10

pluripotential mesenchymal stem cells that become osteoblasts if signaled to do so.

Question 11

Where are osteoblasts located?

Answer 11

surface of the matrix

Question 12

What is the function of osteoblasts?

Answer 12

synthesize, transport and assemble bone matrix and initiate its mineralization

Question 13

How long does mineralization take?

Answer 13

12-15 days

Question 14

What are osteocytes?

Answer 14

former osteoblasts enclosed in the matrix they built and no longer actively building matrix are

Question 15

What are bony canaliculi?

Answer 15

an intricate network of dendritic cytoplasmic processes through tunnels that connect osteocytes

Question 16

What is the function of osteocytes?

Answer 16

help to control calcium and phosphate levels in the microenvironment; detect mechanical forces and translate them into biologic activity (mechanotransduction)

Question 17

How do osteocytes regulate calcium and phosphate levels?

Answer 17

have parathyroid hormone (PTH) receptors and regulate serum calcium and phosphorous by mediating osteoclast activity

Question 18

What are osteoclasts?

Answer 18

specialized multinucleated macrophages, derived from circulating blood monocytes

Question 19

What is the function of osteoclasts?

Answer 19

carry out bone resorption and remodel it

Question 20

How do osteoclasts resorb bone?

Answer 20

attach to bone matrix (via surface integrins) and create a sealed extracellular trench (resorption pit) into which they secrete acid and neutral proteases (predominantly MMPs), which dissolves both the inorganic/organic components of bone

Question 21

What cells express transmembrane receptor RANK?

Answer 21

osteoclast precursors

Question 22

What is RANK?

Answer 22

receptor activator for NF-kB

Question 23

What cells express RANK ligand?

Answer 23

osteoblasts and marrow stromal cells

Question 24

What is osteoprotegerin (OPG)? What does it do?

Answer 24

a secreted “decoy” receptor made by osteoblasts and several other types of cells that can bind RANKL and thus prevent its interaction with RANK

Question 25

What happens when RANK is stimulated by RANK ligand?

Answer 25

activation of the transcription factor NF-kB, which is essential for the generation and survival of osteoclasts

Question 26

What cells produce monocyte colony stimulating factor (M-CSF)?

Answer 26

osteoblasts

Question 27

What is the role of monocyte colony stimulating factor (M-CSF) ?

Answer 27

Activation of the M-CSF receptor on osteoclast precursors stimulates a tyrosine kinase cascade that is crucial for the generation of osteoclasts

Question 28

What is the WNT/beta-catenin pathway?

Answer 28

WNT proteins produced by osteoprogenitor cells bind to the LDL receptor related protein 5 and 6 (LRP5 and LRP6) receptors on osteoblasts and thereby trigger the activation of beta-catenin and the production of OPG (preventing RANK pathway)

Question 29

What inhibits the WNT/beta-catenin pathway? What else does it do?

Answer 29

Sclerostin (produced by osteocytes)- inhibits osteoblast activity in a paracrine manner

Question 30

What is the consequence of mutations in the OPG, RANK, RANKL, and LRP5 genes?

Answer 30

cause congenital diseases of bone metabolism

Question 31

What is the function of Osteopontin?

Answer 31

bridges bone cells and matrix (TRICK QUESTION) does TONS of things

Question 32

What is osteocalcin?

Answer 32

plays a role in bone formation and mineralization and in calcium homeostasis.

Question 33

Why are blood levels of osteocalcin useful?

Answer 33

sensitive and specific marker for osteoblast activity

Question 34

Where is the growth flate in long bones?

Answer 34

epiphysis

Question 35

What is the metaphysis?

Answer 35

are of long bone between diaphysis (shaft) and epiphysis

Question 36

How do bones develop in an embryo?

Answer 36

bones develop from a cartilage mold by a process of endochondral ossification

Question 37

What synthesizes the cartilage mold?

Answer 37

mesenchymal precursor cells

Question 38

What type of bone growth occurs at the primary center of ossification (midshaft)?

Answer 38

radial growth (widening it)

Question 39

What type of bone growth occurs that the secondary center of ossification (ends)?

Answer 39

centrifugal fashion

Question 40

How does the growth plate form?

Answer 40

Eventually, a plate of the cartilage anlage becomes entrapped between the two expanding centers of ossification

Question 41

Who is more likely to get osteomyelitis: adults or children? Why?

Answer 41

Children are more prone to osteomyelitis than adults because of the richer blood supply in growing bone

Question 42

How do flat bones develop?

Answer 42

Intramembranous ossification

Question 43

Do flat bones have a growth plate?

Answer 43

no

Question 44

How does intramembranous ossification work?

Answer 44

bone is made only by osteoblasts, the enlargement of bones is achieved by the deposition of new bone on a preexisting surface

Question 45

What hormone is secreted by the pituitary and acts on resting chondrocytes to induce and maintain proliferation?

Answer 45

Growth hormone

Question 46

What hormone is secreted by the thyroid and acts on proliferating chondrocytes to induce hypertrophy?

Answer 46

Thyroid hormone (T3)

Question 47

What is the name of the locally secreted regulator, made by prehypertrophic chondrocytes that coordinates chondrocyte proliferation and differentiation and osteoblast proliferation?

Answer 47

Indian hedgehog (Ihh)

Question 48

What is the name of the local factor, expressed by perichondrial stromal cells and early proliferating chondrocytes, that activates the PTH receptor and maintains proliferation of chondrocytes?

Answer 48

Parathyroid hormone related protein (PTHrP)

Question 49

What is the name of the family of secreted factors that are expressed at highest levels in the proliferating zone and bind to the receptors Frizzled and LRP5/6 to activate beta-catenin signaling (promote both proliferation and maturation of chondrocytes)?

Answer 49

Wnt

Question 50

What is the transcription factor expressed by proliferating but not hypertrophic chondrocytes that is essential for differentiation of precursor cells into chondrocytes?

Answer 50

SOX9

Question 51

What is the name of the transcription factor involved in chondrocyte and osteoblast differentiation?

Answer 51

RUNX2

Question 52

What chemical leads hypertrophic chondrocytes to inhibit proliferation and promote differentiation?

Answer 52

FGF3

Question 53

What is the term for genetic, congenital and developmental diseases that mess up bone development?

Answer 53

skeletal dysplasias

Question 54

True or False: Skeletal dysplasias lead to premalignant uncontrolled cell proliferation.

Answer 54

FALSE: not pre-malignant

Question 55

What is osteogenesis imperfecta?

Answer 55

a group of diseases primarily involving bone even though they relate to type I collagen, which is prevalent in many other organs.

Question 56

What causes achondroplasia?

Answer 56

gain-of-function mutations in the FGF receptor 3 (FGFR3)

Question 57

What causes AD type of osteopetrosis?

Answer 57

loss-of-function mutations of RANK ligand mess up recruitment and activation of osteoclasts

Question 58

What causes the AR type of osteopetrosis?

Answer 58

Mutations in LRP5 receptor, CA2, CLCN7, etc. that alter osteoclast function

Question 59

What do most of the AR mutations for osteopetrosis lead to?

Answer 59

interfere with the process of acidification of the osteoclast resorption pit, which is required for the dissolution of the calcium hydroxyapatite within the matrix

Question 60

What does deletion of CA2 cause is AR osteopetrosis?

Answer 60

prevents osteoclasts from acidifying the resorption pit and solubilizing hydroxyapatite

Question 61

What does a mutation in CLCN7 cause in AR osteopetrosis?

Answer 61

altered proton pump located on the surface of osteoclasts.

Question 62

Are osteopetrosis bones hard?

Answer 62

NO- they are "rock-like" but are actually more like chalk

Question 63

Is there a treatment for osteopetrosis?

Answer 63

hematopoietic stem cell transplantation, which is effective because osteoclasts are derived from hematopoietic precursors. The normal osteoclasts produced from donor stem cells reverse many of the skeletal abnormalities.

Question 64

What disease is caused by mutation in the homeobox HOXD13 gene?

Answer 64

Brachydactyly

Question 65

What does Brachydactyly do?

Answer 65

produces short, broad terminal phalanges of thumbs and first toes

Question 66

What disease is caused by mutation in transcription factor SOX9 gene?

Answer 66

Campomelic dysplasia

Question 67

What are characteristics of campomelic dysplasia?

Answer 67

causes short bowing long bones, small chest cavity, respiratory failure and sex reversal (46XY with female phenotype)

Question 68

What disease is caused by loss-of-function mutations in the RUNX2 gene?

Answer 68

Cleidocranial dysplasia

Question 69

What are characteristics of Cleidocranial dysplasia?

Answer 69

patent fontanelles, delayed closure of cranial sutures, Wormian bones (extra bones that occur within a cranial suture), delayed eruption of secondary teeth, primitive clavicles and short stature

Question 70

What disease is caused by TBX5 mutation?

Answer 70

Holt-Oram syndrome

Question 71

What are characteristics of Holt-Oram syndrome?

Answer 71

thumb, wrist and forearm bone hypoplasias, and commonly a cardiac atrial septal defect

Question 72

What disease is caused by LMX1B gene mutation ?

Answer 72

Nail-patella syndrome

Question 73

What are characteristics of nail-patella syndrome?

Answer 73

hypoplastic nails, hypo- or aplastic patellas, dislocated radial head and progressive nephropathy

Question 74

What disease is caused by PAX3 gene mutation?

Answer 74

Waardenburg syndrome

Question 75

What are characteristics of Waardenburg syndrome?

Answer 75

different colored eyes, partial albinism, patches of white hair or early graying, hearing loss and constipation

Question 76

What disease is caused by COL2A1 gene for type II collagen (prominent in cartilage)?

Answer 76

achondrogenesis

Question 77

What is the characteristic finding in achondrogenesis?

Answer 77

short trunk

Question 78

What disease is caused by mutations in the COL10A1 gene for type X collagen?

Answer 78

Metaphyseal dysplasia

Question 79

What is the characteristic finding in metaphyseal dysplasia?

Answer 79

short stature

Question 80

What is the most common lethal form of dwarfism?

Answer 80

Thanatophoric dysplasia

Question 81

What disease is caused by a somatic gain-of-function mutation during development in GNAS1?

Answer 81

Fibrous dysplasia

Question 82

What is it called when a GNAS1 mutation occurs during embryogenesis?

Answer 82

McCune-Albright syndrome

Question 83

How do the skeletal manifestations of Fibrous Dysplasia occur?

Answer 83

G s-cAMP mediated interruption of normal osteoblast differentiation from precursors

Question 84

What is it called when a GNAS1 mutation occurs in an osteoblast precursor?

Answer 84

monostotic fibrous dysplasia.

Question 85

What are characteristics of McCune Albright syndrome?

Answer 85

polyostotic fibrous dysplasia plus café-au-lait skin pigmentations and endocrine abnormalities, especially precocious puberty

Question 86

Chromosomal rearrangement fusing USP6 gene to promoters leads to what?

Answer 86

produces excess USP6 protease, excess NF-kB transcription factor and excess MMPs resulting in cystic reabsorption of bone.

Question 87

What is an aneurysmal bone cyst?

Answer 87

tumors characterized by multiloculated blood-filled cystic spaces like a sponge filled with blood