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MSS: post-midterm > Bone cell biology > Flashcards

Bone cell biology Flashcards

1
Q

What are the functions of bone?

A
  • infrastructure
  • bone marrow
  • reservoir for Ca and phosphate
  • specialized connective tissue; composed of cells and matrix (bone is calcified ECM)
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2
Q

What regulates the calcium stored in bone?

A
  • Parathyroid Hormone (PTH) stimulates bone resorption and calcium release, via PTH-induced osteoclasts
  • Calcitonin (from the thyroid) antagonizes this process by inhibiting osteoclasts
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3
Q

What makes up the bone matrix?

A
  • inorganic part (70%)
    • calcium + phosporus= hydroxyapatite
    • hydroxyapatite makes bone hard
    • stores 99% of the body’s Ca
  • organic part (30%); osteoid
    • ​type I collagen (stains eosinic/red)
    • proteoglycans (less than in cartilage)
    • glycoproteins (promote calcification/hydroxyapatite)
      • e.g. osteopontin, osteocalcin, which is bone-specific, and sialoprotein
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4
Q

Compare the mineral/water content, collagen type, and neuronal/vascular structure of bone versus hyaline cartilage

A
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5
Q

What makes an osteoblast?

A

Osteoblasts are specialized fibroblasts that differentiate from mesenchymal stem cells (MSCs) due to growth factors including bone morphogenetic proteins (BMPs)

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6
Q

What is the function of osteoblasts?

A
  • Groups of osteoblasts make osteoid (the bone matrix; type I collagen and glycoproteins)
  • Osteoblasts in the periosteal layer mediate increased width (appositional growth; can be monitored by tetracyclin injections)
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7
Q

What is Runx2?

A

A transcription factor considered as the bone ‘master gene’, without which bone cannot form

(Runx2 and osteocalcin are osteoblast specific)

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8
Q

What is osteomalacia?

A

A condition in which calcification is impaired

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9
Q

What is osteitis fibrosa cystica?

A

A condition where osteoclasts destroy the bone matrix as it is made

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10
Q

What are osteocytes?

A

**differentiated osteoblasts

  • occupy lacunae (similar to cartilage cells), which lie between layers of bone matrix termed lamellae
  • ONE osteocyte per lacuna
  • comprise 90% of all bone cells
  • live a long time (half life ~25 years!)
  • aging is accompanied by significant osteocyte loss
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11
Q

What is the function of osteocytes?

A
  • cytoplasmic processes (dendrites) penetrate the bony matrix via canaliculi, where they bind to all types of bone cells via gap junctions
  • function as endocrine cells
    • regulate mechano-sensation (cell to cell signaling) which regulates bone remodeling
    • modulate the opposing activities of osteoblasts and osteoclasts
  • secrete sclerostin (inhibits Wnt signaling in osteoblasts, thereby stopping growth)
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12
Q

What are osteoclasts?

A
  • large (~50 μm) multinuclear cells (15+ nuclei), formed in the bone marrow by the fusion of monocyte-like cells
  • occupy Howship’s lacunae (partly hollowed-out regions of matrix along the endosteal surface)
  • clamp down onto the matrix via a r_uffled cellular border,_ which forms a microenvironment in which the bone matrix is resorbed
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13
Q

What is the function of osteoclasts?

A
  • destroy bone matrix for remodeling
  • Activated osteoclasts release protons -> lowers pH
  • > dissolves calcium phosphate (hydroxyapatite) -> lysosomes release cathepsin-K (enzyme) into microenvironment
  • Activated by cytokines such as parathyroid hormone (PTH), and are inhibited by the thyroid hormone calcitonin

**osteoclasts overactive in osteoporosis

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14
Q

What is Paget’s disease?

A
  • abnormal osteoclasts cause an abnormally high rate of remodeling
  • results in an over-abundance of relatively weak immature bone termed primary or woven bone
  • afflicts adults over 40 years old
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15
Q

What are the two types of bone?

A
  • compact (cortical)
    • areas of dense bone without cavities
    • ~80% of long bone
  • spongy (cancellous, trabecular)
    • areas in which bone is highly trabeculated and cavitated
    • ~20% of long bone
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16
Q

Contrast long and flat bones

A
  • Long Bones
    • diaphysis (shaft) consisting mostly of compact bone, with spongy bone lining marrow
    • epiphyses “caps” of compact bone surrounding spongy bone
  • Flat Bones
    • calvarial bones of the skull
    • two plates of compact bone surround the diplöe (an area of spongy bone)
17
Q

What are the bone linings and where are the cell types located within them?

A

**periosteum (outer connective tissue layer) and endosteum (inner connective tissue layer)

  • osteoblasts= periosteum (small amt in endosteum)
  • osteocytes= within lacunae of the bony matrix between the periosteum and endosteum
  • osteoclasts= endosteum attached to the bony matrix
18
Q

What is an osteon?

A
  • Osteon= a cylindrical bone subunit
  • Each osteon has concentric lamella of bone
    • lamella have lacunae between them that harbor osteocytes
    • lacunae are connected via canaliculi
    • collagen type I fibers in alternating lamellae are arranged in anti-helical fashion (increases bone strength despite its light weight)
  • The innermost lamella surrounds the Haversian canal
    • Haversian canals are connected perpendicularly via Volkmann’s canals
    • both Haversian and Volkmann contain blood vessels, nerves, and lymph vessels
19
Q

Contrast primary and secondary bone

A
  • primary= “woven”
    • less organized
    • observed in developing or regenerating bone.
  • secondary= “lamellar”/mature
    • found in mature adult bone
20
Q

What are the two ways bone can develop?

A
  • Intramembranous
    • osteoblasts deposit osteoid onto a loose framework of reticular connective tissue
    • FLAT bones
  • Endochondral
    • osteoblasts deposit osteoid onto hyaline cartilage
    • LONG bones
21
Q

Describe how flat bones form

A

**intramembranous ossification (e.g. how fontanelles in neonates are filled-in with bone)

  • bone forms in islands termed ossification centers
  • groups of mesenchymal stem cells (MSCs) condense and differentiate into osteoblasts within a loose framework of reticular connective tissue
  • bone matrix is secreted and calcified upon framework
  • ultimately osteocytes are incorporated into lacunae
22
Q

Describe how long bones form

A

**endochondral ossification

  • osteoblasts deposit bone matrix on pre-existing template of hyaline cartilage
  • begins in the diaphysis (in the primary ossification center)
    • hypertrophy of the cartilage cells
    • osteoblast-mediated bone production on the matrix of calcified cartilage (blasts secrete osteoid -> ossification)
  • At the epiphyses, mostly the same process but some hyaline cartilage is retained as…
    • articular cartilage
    • epiphyseal plate cartilage (allows bone length growth)
23
Q

“How do long bones get long”?

A

Estrogen/testosterone induce the

pituitary to express growth hormone, which in turn induces

the liver to make insulin-like growth factor-1 (IGF-1)

24
Q

What are the 4 zones of long bone?

A
  1. Zone of Cartilage Proliferation (activated by IGF-I)
  2. Zone of Hypertrophy **susceptible to fracture (20% of fractures in children) because of large lacunae
  3. Zone of Calcification; chondrocyte proliferation is inhibited, collagen type X is synthesized, and hydroxyapatite formation begins **this region to be strongly basophilic
  4. Zone of Ossification; osteoblasts make collagen type I, **this area is strongly eosinophilic
25
Q

Describe fracture repair

A

**intramembranous and endochondral ossification both occur;

  1. Macrophages remove debris
  2. Fibroblasts and chondroblasts secrete a fibrocartilaginous callus
  3. Osteoblasts replace fibrocartilaginous callus with bony callus
  4. Primary bone is replaced by lamellar secondary bone (stronger)
26
Q

Describe bone tissue engineering

A

**grafting bone for difficult fractures to help repair (some patients don’t heal due to lack of good bone to take the graft)

  • Possible methods;
    • Implantation of BMP-2 or BMP-7 (peptide growth factors that induce stem cells in marrow into osteoblasts)
    • Implantation of BMP encoded plasmids/ retroviral vectors
    • Implantation of adult mesenchymal stem cells (MSCs) -> can form chondroblasts and osteoblasts
  • In all cases these agents are transplanted within an all-important matrix consisting of natural substances such as collagen type I or artificial biodegradable matrix
27
Q

What stops bone remodeling?

A

NOTHING! It’s an ongoing process; we get a “new skeleton” every 10 years

**Osteoclasts excavate bone which is then replaced by activated osteoblasts

28
Q

Describe osteopetrosis

A

A disease of remodeling that results in dense heavy bone (osteoclasts lack ruffled border)

aka “too much bone”

29
Q

Describe osteoporosis

A

A disease of remodeling where resorption by osteoclasts outpaces osteogenesis= hollow fragile bones

aka “too little bone”

**leptin (hormone made by fat cells) induces the CNS to inhibit bone formation -> connection between osteoporosis and obesity

30
Q

What is the prevalence of osteoporosis? Prevention/screening/treatment?

A
  • most common in post-menopausal women
    • breaks at wrist, hip, spine
  • treatable
    • therapeutic targets= osteoclasts and osteoblasts
  • preventable (dietary Ca/Vit D, weight bearing exercise)
  • screening of BMD (bone mineral density)
31
Q

What is the result of PTH action on stromal cells in the bone marrow?

A

PTH induces mesenchymal stem cells (MSCs) into progenitors that secrete:

  • M-CSF (macrophage colony-stimulating factor)
  • RANK-L (receptor for activator of nuclear factor-kb ligand)
  • osteoprotegerin (OPG)

**these 3 factors act on monocytes

32
Q

What is the function of M-CSF?

A

“macrophage colony-stimulating factor”;

Induces monocyte/macrophage proliferation

33
Q

What is the function of RANK-L?

A

“Receptor for Activator of Nuclear factor-kb Ligand”

Induces osteoclast differentiation

34
Q

What is the function of OPG?

A

“osteoprotegerin”

Antagonizes RANK-L by binding its receptor

**inhibits osteoclast production

35
Q

How do osteoclasts adhere to bone matrix?

A

Via the integrin receptor alpha5beta3, a component of the ruffled membrane (adherence allows them to begin resorptive activity)

**possible target when overactive osteoclasts (e.g. in osteoporosis)

36
Q

Contrast the activating and inhibiting signals for osteoblasts and osteoclasts

A

Theoretically osteoporosis can be managed by regulating these signals (although more complicated in real life)

37
Q

What is the function of Anti-Resorptive Drugs? 3 examples?

A

**inhibit osteoclasts;

  • SERMs (Selective Estrogen Receptor Modulators) such as raloxifene
  • Bisphosphonates (e.g. ibandronate/Boniva)
  • Denosumab, a mAb that binds to RANKL and prevents its binding to receptor
38
Q

What is the function of Anabolic Drugs?

A

**induce osteoblasts;

  • PTH 1-34 (teriparatide/Forteo), a recombinant peptide given via injection
    • “spikes” of PTH via injection favor osteoblasts
    • constant PTH levels favor osteoclasts

MSS: post-midterm (26 decks)

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