Congenital and Developmental Diseases of Bone Flashcards
What are the two components of bone matrix?
osteoid (35%) and inorganic mineral component (65%)
What is the predominant collagen type in osteoid? What are the characteristics of it?
type 1 (triple helix composed of two alpha-1 chains and one alpha-2 chain)
What are the characteristics of type 1 collagen?
calcium hydroxyapatite
What is the role of calcium hydroxyapatite?
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).
What are the two histologic forms of bone matrix?
woven and lamellar
Describe woven bone. When is it made? What does it look like?
Woven bone is rapidly produced during fracture repair, fetal development and various diseases. It has haphazard arrangement of collagen fibers.
Is presence of woven bone in adults normal?
NO–always pathologic
How does lamellar bone differ from woven bone?
it is slowly produced, with collagen fibers in parallel array, which imparts more structural integrity to it than woven bone
What are the 4 cell types in bone?
osteoprogenitor cells, osteoblasts, osteoclasts and osteocytes
What is the function of osteoprogenitor cells?
pluripotential mesenchymal stem cells that become osteoblasts if signaled to do so.
Where are osteoblasts located?
surface of the matrix
What is the function of osteoblasts?
synthesize, transport and assemble bone matrix and initiate its mineralization
How long does mineralization take?
12-15 days
What are osteocytes?
former osteoblasts enclosed in the matrix they built and no longer actively building matrix are
What are bony canaliculi?
an intricate network of dendritic cytoplasmic processes through tunnels that connect osteocytes
What is the function of osteocytes?
help to control calcium and phosphate levels in the microenvironment; detect mechanical forces and translate them into biologic activity (mechanotransduction)
How do osteocytes regulate calcium and phosphate levels?
have parathyroid hormone (PTH) receptors and regulate serum calcium and phosphorous by mediating osteoclast activity
What are osteoclasts?
specialized multinucleated macrophages, derived from circulating blood monocytes
What is the function of osteoclasts?
carry out bone resorption and remodel it
How do osteoclasts resorb bone?
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
What cells express transmembrane receptor RANK?
osteoclast precursors
What is RANK?
receptor activator for NF-kB
What cells express RANK ligand?
osteoblasts and marrow stromal cells
What is osteoprotegerin (OPG)? What does it do?
a secreted “decoy” receptor made by osteoblasts and several other types of cells that can bind RANKL and thus prevent its interaction with RANK
What happens when RANK is stimulated by RANK ligand?
activation of the transcription factor NF-kB, which is essential for the generation and survival of osteoclasts
What cells produce monocyte colony stimulating factor (M-CSF)?
osteoblasts
What is the role of monocyte colony stimulating factor (M-CSF) ?
Activation of the M-CSF receptor on osteoclast precursors stimulates a tyrosine kinase cascade that is crucial for the generation of osteoclasts
What is the WNT/beta-catenin pathway?
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)
What inhibits the WNT/beta-catenin pathway? What else does it do?
Sclerostin (produced by osteocytes)- inhibits osteoblast activity in a paracrine manner
What is the consequence of mutations in the OPG, RANK, RANKL, and LRP5 genes?
cause congenital diseases of bone metabolism
What is the function of Osteopontin?
bridges bone cells and matrix (TRICK QUESTION) does TONS of things
What is osteocalcin?
plays a role in bone formation and mineralization and in calcium homeostasis.
Why are blood levels of osteocalcin useful?
sensitive and specific marker for osteoblast activity
Where is the growth flate in long bones?
epiphysis
What is the metaphysis?
are of long bone between diaphysis (shaft) and epiphysis
How do bones develop in an embryo?
bones develop from a cartilage mold by a process of endochondral ossification
What synthesizes the cartilage mold?
mesenchymal precursor cells
What type of bone growth occurs at the primary center of ossification (midshaft)?
radial growth (widening it)
What type of bone growth occurs that the secondary center of ossification (ends)?
centrifugal fashion
How does the growth plate form?
Eventually, a plate of the cartilage anlage becomes entrapped between the two expanding centers of ossification
Who is more likely to get osteomyelitis: adults or children? Why?
Children are more prone to osteomyelitis than adults because of the richer blood supply in growing bone
How do flat bones develop?
Intramembranous ossification
Do flat bones have a growth plate?
no
How does intramembranous ossification work?
bone is made only by osteoblasts, the enlargement of bones is achieved by the deposition of new bone on a preexisting surface
What hormone is secreted by the pituitary and acts on resting chondrocytes to induce and maintain proliferation?
Growth hormone
What hormone is secreted by the thyroid and acts on proliferating chondrocytes to induce hypertrophy?
Thyroid hormone (T3)
What is the name of the locally secreted regulator, made by prehypertrophic chondrocytes that coordinates chondrocyte proliferation and differentiation and osteoblast proliferation?
Indian hedgehog (Ihh)
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?
Parathyroid hormone related protein (PTHrP)
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)?
Wnt
What is the transcription factor expressed by proliferating but not hypertrophic chondrocytes that is essential for differentiation of precursor cells into chondrocytes?
SOX9
What is the name of the transcription factor involved in chondrocyte and osteoblast differentiation?
RUNX2
What chemical leads hypertrophic chondrocytes to inhibit proliferation and promote differentiation?
FGF3
What is the term for genetic, congenital and developmental diseases that mess up bone development?
skeletal dysplasias
True or False: Skeletal dysplasias lead to premalignant uncontrolled cell proliferation.
FALSE: not pre-malignant
What is osteogenesis imperfecta?
a group of diseases primarily involving bone even though they relate to type I collagen, which is prevalent in many other organs.
What causes achondroplasia?
gain-of-function mutations in the FGF receptor 3 (FGFR3)
What causes AD type of osteopetrosis?
loss-of-function mutations of RANK ligand mess up recruitment and activation of osteoclasts
What causes the AR type of osteopetrosis?
Mutations in LRP5 receptor, CA2, CLCN7, etc. that alter osteoclast function
What do most of the AR mutations for osteopetrosis lead to?
interfere with the process of acidification of the osteoclast resorption pit, which is required for the dissolution of the calcium hydroxyapatite within the matrix
What does deletion of CA2 cause is AR osteopetrosis?
prevents osteoclasts from acidifying the resorption pit and solubilizing hydroxyapatite
What does a mutation in CLCN7 cause in AR osteopetrosis?
altered proton pump located on the surface of osteoclasts.
Are osteopetrosis bones hard?
NO- they are “rock-like” but are actually more like chalk
Is there a treatment for osteopetrosis?
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.
What disease is caused by mutation in the homeobox HOXD13 gene?
Brachydactyly
What does Brachydactyly do?
produces short, broad terminal phalanges of thumbs and first toes
What disease is caused by mutation in transcription factor SOX9 gene?
Campomelic dysplasia
What are characteristics of campomelic dysplasia?
causes short bowing long bones, small chest cavity, respiratory failure and sex reversal (46XY with female phenotype)
What disease is caused by loss-of-function mutations in the RUNX2 gene?
Cleidocranial dysplasia
What are characteristics of Cleidocranial dysplasia?
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
What disease is caused by TBX5 mutation?
Holt-Oram syndrome
What are characteristics of Holt-Oram syndrome?
thumb, wrist and forearm bone hypoplasias, and commonly a cardiac atrial septal defect
What disease is caused by LMX1B gene mutation ?
Nail-patella syndrome
What are characteristics of nail-patella syndrome?
hypoplastic nails, hypo- or aplastic patellas, dislocated radial head and progressive nephropathy
What disease is caused by PAX3 gene mutation?
Waardenburg syndrome
What are characteristics of Waardenburg syndrome?
different colored eyes, partial albinism, patches of white hair or early graying, hearing loss and constipation
What disease is caused by COL2A1 gene for type II collagen (prominent in cartilage)?
achondrogenesis
What is the characteristic finding in achondrogenesis?
short trunk
What disease is caused by mutations in the COL10A1 gene for type X collagen?
Metaphyseal dysplasia
What is the characteristic finding in metaphyseal dysplasia?
short stature
What is the most common lethal form of dwarfism?
Thanatophoric dysplasia
What disease is caused by a somatic gain-of-function mutation during development in GNAS1?
Fibrous dysplasia
What is it called when a GNAS1 mutation occurs during embryogenesis?
McCune-Albright syndrome
How do the skeletal manifestations of Fibrous Dysplasia occur?
G s-cAMP mediated interruption of normal osteoblast differentiation from precursors
What is it called when a GNAS1 mutation occurs in an osteoblast precursor?
monostotic fibrous dysplasia.
What are characteristics of McCune Albright syndrome?
polyostotic fibrous dysplasia plus café-au-lait skin pigmentations and endocrine abnormalities, especially precocious puberty
Chromosomal rearrangement fusing USP6 gene to promoters leads to what?
produces excess USP6 protease, excess NF-kB transcription factor and excess MMPs resulting in cystic reabsorption of bone.
What is an aneurysmal bone cyst?
tumors characterized by multiloculated blood-filled cystic spaces like a sponge filled with blood
