Bone Physiology Flashcards

1
Q

What are the primary functions of bone tissue?

A
  • Support
  • Movement
  • Protection
  • Mineral storage
  • Energy storage
  • Blood cell formation
  • Energy metabolism
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2
Q

What are the two primary components of the ECM (matrix component of bone)?

A
  • Organic components (35% of tissue mass)
  • Inorganic components (65% of tissue mass)
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3
Q

Organic Components of Bone ECM

A
  • Consists of organic substances, primarily collagen, which contributes to the flexibility and tensile strength that allow bone to resist stretching and twisting
  • Also contains: Osteonectin and Osteocalcin, Proteoglycans, Sialoproteins, Osteopontin, and thrombospondin
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4
Q

What is the role of the organic components of the Bone ECM: Osteonectin and Osteocalcin?

A

Aid in hydroxylapatite crystallization and binds calcium

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5
Q

What is the role of the organic component of the Bone ECM: Proteoglycans?

A

Bind growth factors (TGF-β)

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6
Q

What is the role of the organic component of the Bone ECM: Sialoproteins, Osteopontin, and Thrombospondin?

A

Mediate osteoclast adhesion to bone surface (bind osteoclast integrins)

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7
Q

Inorganic Components of Bone ECM

A
  • Consists of inorganic hydroxyapatites or mineral salts, primarily calcium phosphate (some calcium carbonate, K and Mg)
  • present as tiny crystals to lie in and around collagen fibrils in the ECM
  • Pack tightly, contributing to the hardness of bone and its ability to resist compression
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8
Q

Osteogenic Cells

A
  • Stem cells that differentiate into bone-forming osteoblasts
  • Located within the inner layer of the periosteum
  • Precursor to osteoblasts and osteocytes
  • Only bone cells that undergo cell division
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9
Q

What are Osteoblasts derived from?

A

Mesenchymal stem cells

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10
Q

Osteoblasts

A
  • Cuboidal shaped
  • Directly regulate bone matrix synthesis and mineralization (synthesize components of ECM)
  • Indirectly control bone resorption through release of paracrine factors that regulate osteoclasts (RANKL/OPG)
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11
Q

What 3 things can Osteoblasts become?

A
  • Osteocytes: embedded in matrix
  • Bone lining cells: protect inactive bone surfaces
  • Initiate apoptosis
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12
Q

Osteocytes

A
  • Terminally differentiated osteoblasts that have become trapped within newly deposited bone matrix
  • Smaller than osteoblasts and contain projections into the matrix (allows them to interact with the ECM and respond to changes)
  • Respond to mechanical loading by releasing paracrine factors that stimulate and coordinate bone remodeling and calcium release
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13
Q

What are Osteoclasts derieved from?

A

Mononuclear cells in bone marrow

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14
Q

Osteoclasts

A
  • Cells that resorb mineralized bone matrix by secreting acid and lytic enzymes
  • Multinucleated
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15
Q

What controls differentiation of cells into osteoclasts?

A

Receptor Activator of Nuclear Factor κβ (RANKL) which is released from Osteoblasts

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16
Q

What inhibits differentiation of cells into osteoclasts?

A

OPG – sequesters RANKL

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17
Q

Osteogenic Cell
(1) Function:
(2) Location:

A

(1) Develop into osteoblasts
(2) Deep layers of the periosteum and the marrow

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18
Q

Osteoblast
(1) Function:
(2) Location:

A

(1) Bone formation
(2) Growing portions of bone including the periosteum and endosteum

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19
Q

Osteocytes
(1) Function:
(2) Location:

A

(1) Maintain mineral concentration of matrix
(2) Entrapped in matrix

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20
Q

Osteoclasts
(1) Function:
(2) Location:

A

(1) Bone resorption
(2) Bone surfaces and site of old or injured bone matrix

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21
Q

Wolff’s Law

A
  • “bones that bear a lot of weight remodel at a high rate”
  • bone reacts to mechanical functional stress through an adaptive process resulting in a change of its external and internal architecture to better withstand stress
  • if loading on a particular bone increases, the bone will remodel itself over a period of time to withstand greatest strength (to reduce fx) with least amount of material
22
Q

Bone Remodeling

A
  • the internal turnover of mineralized bone matrix – often leads to changes in the architecture of the bone
  • occurs due to changes in stress and changes in hormones
  • it is an ongoing process
  • functions in: repairing microdamage, maintaining strength, maintaining serum calcium in normal physiological range, helps bones heal after a fracture
  • high loading activities produce higher levels of bone remodeling which will increase bone deposition (ex. weight lifting)
23
Q

Basic Remodeling Process (6 Steps)

A

(1) Microdamage or change in mechanical stress on bone matrix
(2) Osteoclast progenitors are activated
(3) Osteoclastic bone resorption occurs
(4) Reversal
(5) Osteoblastic bone formation
(6) Mineralization, osteocytogenesis

Steps:
(1) Osteoblasts sense microcracks
(2) Osteoblasts produce RANKL
(3) RANKL binds to RANKL receptors on nearby monocyte precursor cells, and induces these cells to form osteoclasts
(4) Osteoclasts secrete collagenase which digests collagen protein in organic matrix; leads to formation of “pits” on bone surface called Howship’s Lacunae, and release of Ca2+
(5) Osteoblasts also secrete Osteoprotegerin which binds to RANKL and prevents it from activating RANKL receptors, and they secrete Osteoid Seam which fills in the holes on the surface of the bone (osteoblasts sometimes get stuck in these holes and then they mature to osteocytes and stay in bone)

24
Q

List the regulators (local or systemic) of bone modeling and remodeling

A
  • Transforming Growth Factor- β
  • Bone Morphogenic Proteins (BMPs)
  • Osteoprotegerin (OPG)
  • Fibroblast Growth Factors (FGFs)
  • Insulin-Like Growth Factors (IGFs)
  • Platelet-Derived Growth Factor (PDGF)
  • RANKL
  • Interleukins
  • Parathyroid Hormone (PTH)
25
Q

Transforming Growth Factor- β

A
  • stimulates the proliferation and differentiation of osteoblasts and bone formation
  • increases OPG production
26
Q

Bone Morphogenic Proteins (BMPs)

A
  • potent inducers of osteoblasts and bone formation
  • regulate matrix production
  • can be used clinically in fracture healing and spinal fusion – rhBMP-2
27
Q

Osteoprotegerin (OPG)

A
  • secrete from osteoblasts
  • binds RANKL
  • prevents osteoclast activation
28
Q

Fibroblast Growth Factors (FGFs)

A
  • increases proliferation of osteoblasts
  • enhances callus formation during fracture repair
  • FGF-2 stimulates angiogenesis during fracture repair
29
Q

Insulin-Like Growth Factors (IGFs)

A
  • stimulated by growth hormone (produced in liver)
  • increases bone collagen matrix synthesis and inhibits degradation of collagen
30
Q

Platelet-Derived Growth Factor (PDGF)

A
  • increases collagen synthesis
31
Q

RANKL

A
  • secreted from osteoblasts
  • activates osteoclasts for bone resoprtion
  • regulated by OPG
32
Q

Interleukins

A
  • stimulate bone resorption
  • IL-1 is the most potent
  • IL-1 expression is decreased by estrogen (possible mechanism for post-menopausal bone resorption increases)
33
Q

Parathyroid Hormone (PTH)

A
  • falling blood Ca (hypocalcemia) signals parathyroid gland to release PTH
  • PTH then signals osteoclasts to degrade bone matrix and release Ca into blood
34
Q

Fracture Healing

A
  • involved sequence of inflammation, repair, and remodeling
  • healing sequence depends on the amount of movement between bone fragments – indirect or direct bone healing
35
Q

If there is limited movement (large space) between fractured bone fragments, what type of bone healing occurs?

A

Indirect

36
Q

If there is no movement (not much space) between fractured bone fragments, what type of bone healing occurs?

A

Direct

37
Q

Indirect (Secondary) Fracture Healing

A
  • some but limited movement at fracture site
  • 5 stages:
    (1) Tissue destruction and hematoma (time of fx)
    (2) Inflammatory phase (~1 week): driven by immune cells, cytokines, hormones; helps recruit mesenchymal stem cells from periosteum into area
    (3) Soft callus formation (weeks 2-3): formation of fibrous connective tissue that is first placed at fx site; helps limit movement of bone fragments
    (4) Hard callus formation (weeks 4-12): woven bone replaces the soft callus; eventually the woven bone will be replaced by lamellar bone
    (5) Remodeling of bone (years)
38
Q

Direct (Primary) Fracture Healing

A
  • contact healing between bones
  • no callus is formed
  • requires “absolute” stability between fracture fragments (no motion)
  • bone itself is laid down at fx site; osteoclasts start resorption which is followed by osteoblastic activity which consists of laying down lamellar bone
39
Q

Components of Direct Fracture Healing:

A
  • Contract Healing: occurs if there is direct contact between fragment ends, lamellar bone is placed
  • If gaps are 200-500 nm then woven bone is placed first followed by lamellar bone
  • If gaps are >500 nm then will use indirect healing
40
Q

If gaps are ___nm, indirect healing will take place at fracture site

A

> 500

41
Q

If gaps are __-___nm, woven bone will initially be placed and will eventually be replaced by lamellar bone (no callus formation!)

A

200-500

42
Q

Anti-resorption treatments (help reduce breakdown and demineralization of bone) include:

A
  • Bisphosphonates: inhibit osteoclast activity and induce osteoclast apoptosis
  • Hormone Replacement: typically with Estrogen
  • Selective Estrogen Receptor Modulators
  • Denosumab: a monoclonal Ab against RANKL (similar to OPG in the way it bings to RANKL and prevents it from activating osteoclasts)
43
Q

Anabolic Agents (stimulate bone formation) include:

A
  • BMP-2: induces osteoblast proliferation and activity for increased bone matrix production
  • PTH: only if administered intermittently (daily) help reduce vertebral fxs (saw 70% reduction being reported over untreated pts)
44
Q

List the endocrine regulators of bone:

A
  • Estrogen
  • Thyroid Hormones
  • Glucocorticoids
  • PTH
  • Growth Hormone
45
Q

Estrogen

A
  • direct
  • stimulates fx healing through receptor-mediated mechanisms
  • decreases RANKL production from osteoblasts
  • modulates releases of an inhibitor of IL-1 (results in inhibition of bone resorption)
46
Q

Thyroid Hormones

A
  • direct
  • thyroxine and triiodothyronine stimulate osteoclastic bone resorption
47
Q

Glucocorticoids

A
  • indirect
  • inbibit Ca absoprtion from gut causing increased PTH and therefore, increased orthoclastic bone resorption
48
Q

What happens if there is intermittent exposure to PTH?

A
  • stimulates osteoblasts
  • increases bone formation
49
Q

What happens if there is chronic exposure to PTH (ex. someone with hyperparathyroid)?

A
  • stimulates osteoclasts to break down bone and release Ca
  • can lead to hypercalcemia (elevated serum Ca level)
50
Q

Growth Hormone

A
  • indirect
  • mediated through IGF-1
  • increases callus formation and fracture strength by stimulating osteoblasts (helps with repair and growth)