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Biochem > Lecture 43: Biochemistry of Bone Formation > Flashcards

Lecture 43: Biochemistry of Bone Formation Flashcards

1
Q

what are the 4 phases of skeletal development

A

-migration
- interaction with epithelial cells
-interaction leads to mesenchymal condensation
-followed by differentiation to chondroblasts or osteoblasts

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2
Q

what are the types of bone formation

A

endochondral bone formation and intramembranous bone formation

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3
Q

describe what happens in endochondral bone formation

A

indirect- mesenchyme forms cartilage template first which is later replaced by bone

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4
Q

where does endochondral bone formation occur

A

-in most bones of the skeleton especially bones that bear weight and have joints
- fracture repair sites

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5
Q

describe intramembranous bone formation

A

direct transformation of mesenchymal cells to osteoblasts

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6
Q

where does intramembranous bone formation occur

A
  • cranial vault, some facial bones, parts of mandible and clavicle
    -fracture repair sites
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7
Q

how do blood vessels invade the forming bone

A

VEGF produced by hypertrophic chondrocytes

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8
Q

when does the secondary ossification center appear

A

around the time of birth

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9
Q

what is the mechanism by which intramembranous ossification works

A

-mesenchymal cells condense to produce osteoblasts which deposit osteoid
- osteoid matrix calcifies/osteoblasts become arranged along calcified region of the matrix
- some osteoblasts trapped in bone matrix become osteocytes

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10
Q

what is the first type of bone produced developmentally

A

woven bone

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11
Q

when is woven bone produced

A

when osteoblasts need to form bone rapidly such as in embryonic development, fracture healing, and disease states

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12
Q

what is immature woven bone remodeled and replaced with

A

lamellar bone

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13
Q

describe woven bone

A

-disorganized structure
-randomly oriented collagen fibrils
-increased cell density
-reduced mineral content

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14
Q

describe lamellar bone

A

-highly organized
-bone lamellae concentrically arranged around central canal containing blood vessels and nerves
-parallel oriented collagen fibrils
-mechanically stronger

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15
Q

what is lamellar bone further classified into

A

compact (cortical) bone and cancellous (spongy) bone

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16
Q

what is another name for woven bone? lamellar bone?

A

woven - primary
lamellar - secondary

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17
Q

what are they 3 types of bone cells

A

osteoclasts, osteoblasts, osteocytes

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18
Q

what do osteoblasts, chondrocytes, myoblasts and adipocytes all differentiate from

A

a common mesenchymal progenitor

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19
Q

where are osteoblasts located

A

cuboidal cells of bone forming surfaces

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20
Q

what do osteoblasts produce

A

large amounts of ECM proteins (especially type 1 collagen) called osteoid which then mineralized

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21
Q

what is the lifespan of osteoblasts

A

weeks

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22
Q

what are transcription factors for osteoblasts

A

RUNX2 and Osterix

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23
Q

what are the ECM proteins that make up osteoblasts

A

type 1 collagen, osteopontin, osteocalcin, bone sialoprotein (BSP)

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24
Q

what pathway do RUNX2 and Osterix work in

A

beta catenin

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25
Q

what is RUNX2 essential for

A

bone and tooth development

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26
Q

what does a heterozygous mutation of RUNX2 result in

A

cleidocranial dysplasia

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27
Q

what are the symptoms of cleidocranial dysplasia

A

-autosomal dominant
- delayed ossification of midline structures
- clavicles partly or completely missing
-late closing of fontanelle
- supernumerary teeth
-prognathic mandible due to hypoplasia of maxilla

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28
Q

what transcription factor does RUNX2 induce

A

Osterix

29
Q

what osteoblast genes does osterix control expression of

A

-type 1 collagen
-osteocalcin
-osteopontin

30
Q

what are mutations in osterix associated with

A

osteogenesis imperfecta type 7

31
Q

what are some key signaling pathways that regulate osteoblast differentiation

A

BMPs, WNT/Beta catenin,

32
Q

what are BMPs

A

originally purified from bone extracts that induce bone formation when implanted in muscle

33
Q

what are BMPs required for

A

skeletal development/maintenance of adult bone homeostasis

34
Q

what do BMPs do

A

-promote differentiation from early osteoprogenitor cells
-fracture healing

35
Q

what do mutations in BMPs lead to

A

skeletal defects/disorders

36
Q

what is fibrodysplasia ossificans progressiva (FOP)

A

heterotrophic bone formation (bone forming in soft tissues)

37
Q

what happens in FOP

A

-ribbons, sheets, plates of bone in extra skeletal sites - fuses joints, ribs
- bone forms in response to tissue trauma

38
Q

what mutation is involved in FOP

A

BMP type 1 receptor

39
Q

what does a mutation in the BMP type 1 receptor in FOP do

A

causes mild constitutive activation and overactivation with BMP ligand binding
-acquired responsiveness to activin A

40
Q

what is the Wnt/ beta catenin pathway important in

A

determining bone mass

41
Q

what do activating mutations in Lrp5 lead to

A

high bone mass in humans

42
Q

what do inactivation mutations in Lrp5 lead to

A

low bone mass

43
Q

what is the first phase of mineralization initiated by

A

matrix vesicle

44
Q

what does the second phase of mineralization involve

A

propagation of mineralization on collagen fibers

45
Q

what are matrix vesicles

A

extracellular membrane bound vesicles produced by osteoblasts

46
Q

what do matrix vesicles contain

A

transporters and enzymes involved with the generation of phosphate and uptake of calcium and phosphate into the vesicle to reach high enough concentrations to initiate mineralization

47
Q

where is alkaline phosphatase highly expressed

A

in osteoblasts and odontoblasts

48
Q

what does alkaline phosphatase do

A

hydrolyzes pyrophosphate which is a natural inhibitor of mineralization- thereby increasing local phosphate concentration, promoting mineralization

49
Q

what are mutations in the alkaline phosphatase gene associated with

A

hypophosphatasia

50
Q

what is hypophosphatasia

A

rare heritable rickets/osteomalacia

51
Q

what is hypophosphatasia caused by

A

mutation in human alkaline phosphatase gene -TNSALP

52
Q

what is HPP characterized by

A

impaired mineralization of skeleton/dentition, leg bowing, rachitic rosary, early tooth loss, waddling gait, muscle weakness, seizures

53
Q

what are ENPP1 mutations associated with

A

syndrome of spontaneous infantile arterial and periarticular calcification

54
Q

a mutation in what components will affect mineralization

A

ENPP1, TNSALP, Anx5, PHOSPHO1

55
Q

what are osteocytes

A

terminally differentiated osteoblasts embedded in bone matrix

56
Q

what percentage of bone cells are osteocytes

A

over 90%

57
Q

what is the lifespan of osteocytes

A

decades

58
Q

are osteocytes quiescent cells

A

no they are active cells with key functions in bone

59
Q

what is the transcription factor of osteocytes

A

Mef2c

60
Q

what are the early osteocyte markers

A

-E11/gp38/podoplanin
-dentin matrix protein-1 (DMP1)
- matrix extracellular phosphoglycoprotein (MEPE)
- phosphate regulating endopeptidase homolog, X linked (PHEX)

61
Q

what is the late osteocyte marker

A

sclerostin (SOST)

62
Q

what are some potential functions of osteocytes

A

-mechanosensors
-control bone resorption and bone formation
-regulate mineralization
-regulators of mineral homeostasis- both calcium and phosphorus
-regulate activity of osteoblasts and osteoclasts

63
Q

what is sclerostin expressed in

A

mature osteocytes, cementocytes, odontoblasts

64
Q

what does sclerostin do

A

antagonizes Wnt/beta catenin signaling pathway , limits bone formation

65
Q

what does the deletion or mutation of SOST gene result in

A

sclerosteosis or Van Buchem’s disease

66
Q

what happens in Sclerosteosis

A

increased bone mass, especially obvious in craniofacial skeleton

67
Q

what genes do osteocytes express that are important in phosphate homeostasis

A

FGF23
DMP1
PHEX

68
Q

what endocrine role do osteocytes play

A

regulation of phosphate homeostasis

Biochem (34 decks)

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