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BMS 460 > Bone Remodeling > Flashcards

Bone Remodeling Flashcards

1
Q

define bone remodeling

A
  • replacement of old bone with newly formed bone by a resorption-production sequence
  • this depends on closely coupled activities of osteoclasts and osteoblasts
  • continuous throughout life, happens at random spots
  • establishes optimum bone strength by repairing microcracking, also maintains calcium homeostasis
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2
Q

4 steps of bone remodeling and what they do

A
  1. activation: osteoblast precursors get recruited to haversian canal, then differentiate into osteoclasts. the osteoclasts lining the bone lamella facing the canal start bone resorption process of the inner lamella, moving through consecutive lamellae towards outer lamella. interstitial lamellae (holes?) are residuals of the remodeling osteon
  2. resorption: more osteoclast precursors are recruited as lamellar resorption progresses beyond the original osteon. when osteoclasts stop the resorption process, they reverse back to osteoblasts
  3. reversal: osteoblasts organize a layer inside the resorption cavity and secrete osteoid. the cement line indicates the boundary of the newly organized lamella. new lamellae keep getting deposited towards the center of the osteon
  4. formation: osteoblasts keep depositing bone, and some will get trapped in the matrix and become osteocytes. this forms a new osteon/haversian system
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3
Q

what is the haversion canal and connect it to resorption/formation?

A
  • the center of the osteon where blood vessels reside
  • resorption goes away from the canal
  • formation goes towards the canal
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4
Q

what happens with the balance of resorption and formation in osteoporosis?

A

more bone is reabsorbed than is subsequently formed

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5
Q

what allows communication between osteoblasts and osteoclasts?

A
  • hormones
  • cytokines
  • growth factors
  • signal-transducing molecules
  • remember, bone resorption and formation are coupled processes and they are controlled by systemic factors and local cytokines. some of these get deposited into the bone matrix and are thus released upon resorption
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6
Q

talk through the chart on slide 27

A
  • start with osteoclasts
  • they will resorb bone (when they sense microdamage), which will liberate matrix-bound growth factors
  • these growth factors will facilitate proliferation of osteoprogenitor cells
  • Runx2, Wnt and BMP will cause these osteoprogenitor cells to differentiate into active osteoblasts
  • these osteoblasts express LRP5/6 and beta-catenin
  • some osteoblasts will become osteocytes when they get trapped in the matrix
  • surface osteoblasts will be affected by mechanical factors, hormones, and cytokines (which will also induce the osteoprogenitor cells)
  • as a result, surface osteoblasts will activate osteoclast precursors, increasing osteoclasts. the whole cycle continues
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7
Q

overall role of vitamin D and PTH in osteoclastogenesis

A
  • vitamin D and PTH stimulate osteoblasts to secrete factors that are needed for osteoclastogenesis
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8
Q

go through the process of osteoclastogenesis (slide 28)

A
  1. a monocyte (from bone marrow) gets to a spot where bone formation and remodeling needs to occur. it expresses M-CSF receptor on its surface
    2/3. monocyte becomes a macrophage. its M-CSF receptor binds M-CSF ligand, which is released from osteoblasts. this binding causes the macrophage to express RANK, which binds RANKL on the surface of osteoblasts. this binding commits the macrophage to osteoclastogenesis
    - the mononucleated monocyte becomes a multinucleated osteoclast precursor. it still can’t reabsorb bone
  2. RANK-stimulated osteoclastogenesis is inhibited by osteoprotegerin (blokcs RANKL from binding RANK
  3. the resting/nonfunctional osteoclast uncouples from osteoblast (they were bound together via RANK-RANKL
  4. osteoclasts are mature when they have the sealing zone and ruffled border, which requires alpha-v-beta-3 integrin to develop
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9
Q

how do osteoblasts regulate population of functional osteoclasts?

A

osteoblast secretes osteoprotegerin, which stops RANKL on osteoblast from binding RANK on osteoclast precursor, so it can’t develop into a mature osteoclast

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10
Q

how exactly does PTH affect the bone resorption process?

A

PTH stimulates M-CSF ligand and RANKL expression in osteoblasts

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11
Q

what needs to be balanced for osteoclastogenesis?

A
  • osteoprotegerin and RANKL!
  • these come from osteoblasts
  • hypercortisolism impairs balance
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12
Q

abnormal function of osteoclasts results in…

A

there are many manifestations, but essentially bone remodeling is absent

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13
Q

osteopetrosis

A
  • “stone-like” bone
  • this includes a bunch of hereditary diseases
  • bone is abnormally brittle and the marrow canal is not developed
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14
Q

describe the steps of osteoclast function (slide 29)

A
  1. around the circumference of the ruffled border (where plasma membrane is almost touching bone), actin filaments accumulate to form a sealing zone (alongside alpha-v-beta-3 integrin (binds osteoclast to bone) and osteopontin)
  2. chloride channelprevents rise of intracellular pH and allows chloride to enter the osteoclast
  3. bicarbonate is exchanged for chloride, which is produced from the carbonic anhydrase rxn between water and carbon dioxide. this bicarbonate-chloride exchanger maintains cytoplasmic electroneutrality
  4. the rxn above also makes protons, which get released into howship’s lacuna via an H+-ATPase pump (there are chloride channels here too, so chloride leaves, so essentially HCl is made by osteoblast)
  5. the protons solubilize mineralized bone (hydroxyapatite)
  6. cathepsin K is also released from osteoclast into howship’s lacuna and degreades exposed organic matrix (collagen and noncollagenous proteins), which become exposed after the mineral part of bone (hydroxyapatite) gets solubilized
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15
Q

what is the howship lacuna?

A
  • where the bone and the ruffled border of the osteoclast meet
  • also called subosteoclastic compartment
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16
Q

osteopetrosis

A
  • mutation in M-CSF gene
  • this means there is abnormal osteoclast differentiation, so bone will not be resorbed because there will be insufficient numbers of osteoclasts
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17
Q

marble bone disease

A
  • clinical variant of osteopetrosis
  • deficiency in carbonic anhydrase II
  • in xray on slide: structure of the humerus shows thickening of the cortex and small size of the medullary canal
  • causes exophthalmos (bulging eyes), deafness, facial paralysis, speech impediment
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18
Q

how common is cancer metastasis to bone?

A
  • it is a serious complication for about 70% of people with advanced breast or prostate cancer
  • also happens in 15-30% of people with lung cancer
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19
Q

how can bone metastases be described/categorized?

A
  • osteolytic: occur due to activation/activity of too many osteoclasts
  • osteoblastic: occur because of osteoblasts getting activated and therefore too much bone gets deposited
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20
Q

factors that account for frequent bone metastasis

A
  • tumor cells express many humoral factors that stimulate osteoclast formation
  • tumor cells get to the bone marrow quickly because the bone marrow is rich in blood flow
  • tumor cells stimulate neovascularization and more tumor growth, which is possible because bone is a repository for many growth factors that get liberated locally when osteolysis occurs
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21
Q

describe steps of osteolytic bone disease

A
  1. metastatic tumor cells release factors that stimulate osteoclastic recruitment and differentiation
  2. osteoclasts break down bone
  3. bone resorption causes growth factors to get liberated, stimulating tumor growth
  4. tumor continues to proliferate, making more substances that increase osteoclast-mediated bone resorption
  5. process continues
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22
Q

describe steps of osteoblastic bone disease

A
  1. metastatic tumor cells release growth factors that stimulate activity of osteoclasts
  2. tumor cells also release growth factors that stimulate activity of osteoblasts
  3. excessive bone formation happens around tumor cell deposits (osteosclerosis)
  4. osteoclastic activity liberates growth factors that stimulate tumor cell growth
  5. osteoblastic activation releases unidentified osteoblastic growth factors that also stimulate tumor cell grown
  6. essentially, activation of both osteoclasts and osteoblasts causes increase in growth factors that stimulate tumor cell growth!
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23
Q

what is PTHrP

A
  • parathyroid hormone-related peptide
  • it is encoded by a gene that is completely different from the PTH gene
  • can cause hypercalcemia in some malignancies
  • made by a wide variety of normal and malignant tissues (whereas PTH is only made in the parathyroid!)
  • PTHrp mimics actions of PTH on kidney and bone. the PTH 1R receptor in kidney and bone recognizes PTHrP with a similar affinity as it has to PTH
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24
Q

bone resorption in multiple myeloma

A
  • multiple myeloma is clonal proliferation of neoplastic plasma or their cells
  • or it can be differentiation of precursors to neoplastic plasma cells that are committed to plasmacytic differentiation
  • multiple myeloma cells produce pro-osteoclastogenic cytokines like IL-3, macrophage inflammatory protein-1 alpha and beta, and TNF-alpha
  • this process can be extramedullary or solitary, and usually forms multiple foci of plasma cell proliferation
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25
Q

what is a major characteristic of lesions in multiple myeloma patients?

A

multiple myeloma lesions are only osteolytic (whereas most cancer patients have both osteolytic and osteoblastic types of lesions)

26
Q

what do myeloma cells produce?

A
  • DDK1: a secreted inhibitor of beta-catenin-dependent Wnt signaling (this inhibits osteoblasts, thus inhibiting new bone formation)
  • RANKL: This binds RANK receptors on osteoclasts, causing them to become activated
27
Q

what does estrogen normally do?

A
  • inhibits production and action of osteoclasts
  • enhances osteoblasts
  • this results in net bone formation!
28
Q

what does estrogen deficiency lead to?

A
  • increased osteoclastic activity
  • decreased osteoblastic activity
  • this means more bone resorption and less bone formation - osteoporosis!
29
Q

what does hypercortisolism do to bone remodeling?

A
  • glucocortocoids increase RANKL production
  • they decrease osteoprotegerin production by osteoblasts
  • this overall leads to bone loss - osteoporosis!
30
Q

what are the two causes of osteoporosis that we talked about?

A
  • estrogen deficiency
  • hypercortisolism
31
Q

osteoporosis epidemiology

A
  • most common metabolic bone abnormality
  • loss of organic bone matrix and minerals, decreasing thickness and density of bone
  • more common in women than men, partially because men have greater bone mass to start with so it takes longer for them to develop osteoporosis
32
Q

primary classification of osteoporosis

A
  • estrogen related
  • this is the most common type
  • it is idiopathic in children and young adults
  • it is also the postmenopausal type
  • and the senile type in men and women
33
Q

secondary classification of osteoporosis

A
  • due to an underlying disease, could be hypercortisolism or renal disease for example
  • other examples include drugs, hypogonadism, malnutrition, space travel
34
Q

prevention of osteoporosis

A
  • calcium and vitamin D supplements
  • stop smoking (because smoking inhibits osteoblast activity)
  • add weight-bearing exercise
35
Q

relate diabetes mellitus to osteoporosis

A
  • diabetes mellitus can involve nephropathy
  • nephropathy can come from hardening of the kidney (nephrosclerosis)
  • this causes an imbalance in calcium homeostasis, which can lead to osteoporosis
36
Q

treatment for osteoporosis

A
  • bisphosphonates: inhibit bone resorption
  • antibodies against RANKL: inhibit osteoclastogenesis
  • calcitionin and estrogen supplementation: inhibit osteoclast function
37
Q

what does chronic renal disease do in terms of bones?

A
  • disrupts renal handling of calcium and phosphate
  • overall, results in osteoporosis and calcifications
  • end-stage renal disease is a major cause of secondary hyperparathyroidism
38
Q

what does nephropathy do in chronic renal disease to affect the parathyroid?

A
  • nephropathy results in failure to absorb calcium, which leads to hypocalcemia
  • hypocalcemia leads to too much PTH production (secondary hyperparathyroidism)
  • PTH leads to differentiation and proliferation of osteoclasts
  • these osteoclasts will degrade bone to release calcium into extracellular fluid
  • however, the dysfunctional kidneys cannot reabsorb this calcium, so it will all just get excreted
  • this leads to even more PTH excretion, and the cycle continues (there is a feedback loop between decreased calcium and increased PTH excretion)
  • over time, bone gets degraded so much that it becomes fragile and breaks easily
39
Q

what does end-stage renal disease do to affect the parathyroid gland?

A
  • failing kidneys don’t excrete enough phosphate
  • they also do not convert enough vitamin D to calcitriol
  • any calcium present will combine with the excess phosphate, forming calcium phosphate, which is insoluble
  • this also takes away from calcium even more because there is already very little being absorbed in the gut since vitamin D is not being activated
  • result is hypocalcemia, which leads to secondary hyperparathyroidism
  • over time, bone will be resorbed (osteoporosis) due to too much PTH, which will cause bones to be calcified and fragile
40
Q

review charts on left side of slide 34

A

YOU MUST

41
Q

what are the types of secondary hyperparathyroidism that we talked about?

A
  • we talked about it caused by renal disease
  • also how it can be caused by nutritional deficiencies/excesses
  • no matter how it is caused, it can cause osteoporosis
42
Q

how can someone get nutritional secondary hyperparathyroidism?

A
  • either inadequate vitamin D3 OR excessive phosphorus in the diet
  • this can lead to long-term over-stimulation of the parathyroid glands (too much PTH long-term)
  • causes generalized skeletal demineralization
  • in advanced stages, there can be maxillary abnormalities because of osteoid deposition and proliferation of fibrous connective tissue
  • this causes limb distortion by palpable fractures without mineralized calluses
  • fibrous connective tissue comes because osteoid is poorly mineralized?
43
Q

what are the three things that ossification requires?

A
  • growth
  • modeling
  • remodeling
  • these processes are mediated by osteoclasts and osteoblasts
  • these cells are under the control of local regulatory factors and blood-borne signaling molecules like PTH and vitamin D
44
Q

rickets and osteomalacia main points

A
  • group of bone diseases characterized by defects in mineralization of bone matrix (osteoid)
  • these are usually caused by vitamin D deficiency, decreased activation of vitamin D to calcitriol, or decreased receptors for calcitriol
45
Q

rickets

A
  • observed in children
  • causes skeletal deformities
46
Q

hereditary vitamin D-resistant rickets

A
  • rare type of rickets
  • caused by mutation of calcitriol receptor
  • calcitriol can’t increase calcium absorption, lack of calcium means bone can’t get mineralized
47
Q

osteomalacia

A
  • observed in adults
  • caused by poor bone matrix mineralization
48
Q

describe the mechanism of the antirachitic effect of calcitriol

A
  • firslty, this means it is “anti-rickets”
  • calcitriol increases calcium and phosphate absorption in gut
  • kidneys make sure they are balanced, and they can get deposited in bone
  • this increases bone mineralization
49
Q

pneumonic for manifestations of tumors that cause hyperparathyroidism

A

“broken bones, kidney stones, abdominal groans, and psychic moans”

50
Q

what are the four organs that we saw a parathyroid adenoma can affect?

A
  • first of all, this adenoma causes too much PTH secretion
  • brain/psychological state
  • pancreas/gallbladder
  • kidneys
  • bones
51
Q

parathyroid adenoma and bones

A
  • osteoporosis
  • osteitis fibrosa cystica
  • fractures
  • basically, too much PTH causes bone resorption because it wants to increase extracellular calcium levels
52
Q

parathyroid adenoma and kidneys

A
  • nephrolithiasis
  • nephrocalcinosis
  • polyuria
53
Q

parathyroid adenoma and pancrease/gallbadder

A
  • gallstones
  • peptic ulcer
  • acute pancreatitis (possibly caused by gallstones?)
54
Q

two molecular affects in sporadic adenomas?

A
  • cyclin D1 inversion (segment of a chromosome is reversed and positioned next to PTH gene)
  • MEN1 mutation
55
Q

what can hypoparathyroidism lead to?

A
  • causes hypocalcemia because not enough PTH, so body thinks that extracellular calcium levels are high or at least normal
  • hypocalcemia opens up sodium channels in excitable cell membranes
  • this causes depolarization and spontaneous firing of action potentials
  • this causes spasms: hypocalcemic tetany
56
Q

how to treat hypoparathyroidism?

A

treat with PTH (can be injectables or nasal spray)

57
Q

developmental cause of hypoparathyroidism

A

digeorge syndrome: absent parathyroid glands and thymus

58
Q

genetic cause of hypoparathyroidism

A

activating mutations of CaSR: chief cells think that calcium levels are always high, so parathyroid gland doesn’t secrete PTH

59
Q

autoimmune cause of hypoparathyroidism

A

targets CaSR, constantly activating it, which decreases PTH secretion

60
Q

iatrogenic cause of hypoparathyroidism

A

accidental removal of normal parathyroid glands during thyroidectomy

61
Q

idiopathic cause of hypoparathyroidism

A

tissues fail to respond to PTH, we don’t know why

BMS 460 (34 decks)

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