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Locomotor > Bone Function, Structure and Development 2 > Flashcards

Bone Function, Structure and Development 2 Flashcards

1
Q

What is bone remodelling important for?

A
  • Removal of small bone increments which are replaced by new bone
  • Maintains the mechanical integrity of the skeleton: removal of microdamage bone, reinforcement of bone in areas subject to increased mechanical stress
  • Calcium homeostasis
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2
Q

How often does bone remodelling take place?

A
  • Occurs throughout life
  • 5-15% of bone surface normally remodelling in adults
  • 18% of skeleton replaced each year in adults (cancellous bone 20%, cortical bone 2%, iliac crest> distal femur)
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3
Q

What does the basic multicellular unit consist of?

A
  • Osteoclasts
  • Osteoblasts
  • Osteocytes
  • Bone lining cells
  • Blood vessel endothelium
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4
Q

What are the phases of the bone remodelling cycle?

A
  • Activation
  • Resorption (6 weeks)
  • Reversal (1.5 weeks)
  • Formation/ Mineralisation (5 months)
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5
Q

What chemicals are involved in the regulation of bone remodelling?

A 
Mechanical Loads
Systemic hormones:
-PTH, Vit D
-Endocrine hormones (GH, Oestrogen)
Locally produced cytokines
-IL1, IL6
-TNF
-TGFb
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6
Q

Describe the activation phase of the bone remodelling cycle

A

Bone lining cells
-Become rounded, expose bone
-Secrete collagenase to remove a thin covering layer of Unmineralised bone (osteoid)
Osteoclasts recruited
-Differentiate from mononuclear precursors
-RANK ligand-RANK interactions
Control
-Microfractures
-Mechanical stresses (osteocytes secrete sclerostin osteocytes leading to increased RANKL expression, leads to increased OC activity and decreased OB activity)

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7
Q

What are RANK interactions?

A

RANK:
-cell membrane receptor expressed by osteoclasts and precursors
-activated following binding to RANKL expressed stromal cells, osteocytes and osteoblasts
-regulates osteoclast formation and activity
Osteoprotegerin (OPG) decoy receptor that blocks RANK-RANKL interactions

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8
Q

Describe the resorption phase of the bone remodelling cycle

A
  • Osteoclasts adhere to mineralised bone via aVbeta3, the integrin vitronectin receptor
  • Form ruffled border= increases surface area available for secretion/ absorption
  • Secrete acid (removal of Ca hydroxyapatite) and proteases (removal of organic matrix)
  • Production of biomarkers: Urinary or serum collagen type 1 cross-linked C-telopeptide (CTX), bone sialoprotein (BSP), tartrate-resistant acid phophatase
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9
Q

How does the amount of bone resorbed related to osteoclast life span?

A
  • Positively regulated by RANK/RANKL, cytokines including TGFb, BMPs, FGFs and IGFs produced locally or released from bone, systemic hormones such as PTH, maintenance of the ruffled border
  • Negatively regulated by local production of OPG and systemically by calcitonin
  • Osteoclasts die by apoptosis= inhibition of RANK-RANKL interactions
  • Replaced by mononuclear cells
  • Mononuclear cells lay down a cement line to which newly produced osteoid adheres
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10
Q

Describe the reversal phase of the bone remodelling cycle

A
  • The transition from bone resorption to formation is mediated by osteoclast-derived ‘coupling factors’ which direct the differentiation and activation of osteoblasts in resorbed lacunae to refill it with mew bone
  • Osteoblasts differentiate from bone marrow stromal cells
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11
Q

What are the roles for osteoclasts?

A
  • Release of bone matrix derived factors (BMP, IGF) which increase OB formation
  • Cell surface EphrinB2 binds OB EphB4 increasing OB differentiation
  • S1P released by OClasts increased OB migration
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12
Q

Describe the formation phase of bone remodelling

A

Osteoblasts lay down osteoid
-Directional secretion of type 1 collagen
-Non collagenous proteins= osteocalcin, IGF, BMPs that regulate osteoclast/ osteoblast formation and function
Osteoid mineralisation= 15-20 day lag time
Osteocyte formation
-Sclerostin- produced by osteocytes is an inhibitory factor for bone formation

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13
Q

Describe bone mineralisation

A
  • 75% occurs over several days
  • Deposition of Hydroxyapatite Ca10(PO4)6(OH)2= inorganic mineral of bone, precipitate of soluble Ca2+ and iPO4
  • Ratio of Ca2_ and iPO4 in hydroxyapatite changes with time= bone harder but more brittle
  • Other ions may be absorbed or substituted and modify calcification= fluoride, aluminium
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14
Q

How are matrix vesicles involved in bone mineralisation?

A
  • Cytoplasmic buds which have accumulated Ca2+ and iPO4 are released from the surface of osteoblasts = contain alkaline phosphatase, phospho-1
  • MV are deposited on collagen fibres in associated with non-collagenous proteins which mediate crystal nucleation
  • Membrane rupture/ breakdown and the modulation of ECM composition further promote propagation of hydroxyapatite
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15
Q

Describe local regulation of bone mineralisation

A

Predominantly by extracellular PPi

  • Direct binding to growing hydroxyapatite crystals preventing the apposition of mineral ions
  • Induction of osteopontin, a protein that has mineral-binding and crystal growth-inhibiting activity, expression by osteoblasts
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16
Q

Describe systemic regulation of bone mineralisation

A

By endocrine regulators of blood calcium and phosphate levels
-predominantly parathyroid hormone (increases serum Ca2+, decreases Pi)
-vitamin D (increases serum Ca2+)
-FGF23 (produced by osteocytes and osteoblasts in response to increased 1-25(OH)2D3, increases renal excretion of Pi decreases PTH and vitamin D levels)
which form the ‘intestine-bone-kidney-parathyroid gland feedback loop’

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17
Q

What are the chemicals involved in bone remodelling and mineralisation?

A

Major hormonal regulators of osteoclastic bone resorption
-PTH(+ve), calcitonin(-ve) and oestrogen(-ve)
Major hormonal regulators of osteoblastic bone formation
-PTH(+ve), vitamin D3(+ve), calcitonin(-ve), oestrogen(+ve), growth hormone(+ve)

18
Q

What are the types of Metabolic Bone Diseases?

A

Disorders of Bone Remodelling
-Osteoporosis: Resorption> Formation
-Paget’s Disease of Bone: Resorption and Formation increased
-Osteopetrosis: Resorption decreased
Disorders of Mineralisation
-Hyperparathyroidism
-Vitamin D deficiency (osteomalacia, rickets)
-Tumour induced osteomalacia- increased levels of FGF23
-Renal osteodystrophy

19
Q

What is Osteoporosis?

A
  • A progressive bone disease characterized by a decrease in bone mass and density which can lead to an increased risk of fracture
  • Cumulative imbalance of bone remodelling resulting increased bone loss over bone production
20
Q

What does Osteoporosis result from?

A
  • Age related changes in bone cell function and activity
  • Reduced physical activity= increased osteocyte sclerostin production= inhibition of Ob activity
  • Hormonal influences- oestrogen deficiency= increased Oclast activity decreased Ob activity
21
Q

Describe the age related changes in bone mass

A
  • Bone mass increases until early adulthood= peak bone mass
  • Plateau’s for 10-20 years
  • Gradual loss of bone with age= 0.7% per year, M=F, no racial differences
  • Post-menopausal acceleration of bone loss in females
22
Q

What is peak bone mass determined by?

A

Achieved by young adulthood

  • Genetic factors
  • Physical activity
  • Muscle strength
  • Diet: calcium intake during adolescence
  • Hormonal state
23
Q

How is Osteoporosis linked to bone mass?

A
  • Decrease in bone mass with age leads to an increase in fracture risk
  • Lower ‘peak bone mass’ leads to increased fracture risk with normal age related bone loss
  • Accelerated bone loss: female menopause (oestrogen loss), malnutrition, immobilisation, medical disorders (endocrine), medication
24
Q

What is Osteoporotic bone?

A
  • Thinner cortical bone
  • Trabecular bone- struts thinner and less connected
  • Mechanically weak
  • Normally mineralised
25
Q

What is Paget’s Disease of Bone?

A
  • Abnormal localised bone remodelling
  • Clinical features: weak deformed bones, enlarged skull, nerve compression (deafness)
  • Pathology: exaggerated bone remodelling (increased osteoclastic and osteoblastic activity), lytic mixed and sclerotic phases, large multinucleated osteoclasts
26
Q

How is Paget’s Disease genetically linked?

A
  • Most cases are spontaneous
  • Familial clusters with 40% autosomal dominant transmission
  • Mutations identified in at least 4 genes most important is an activating mutation in SQSTM1 (abnormal osteoclast function, increased bone resorption)
27
Q

What is Osteopetrosis?

A
  • Marble bone disease and Albers-Schonberg disease
  • Hard, dense bone
  • Decrease in number or activity of osteoclasts
  • Number of causes= carbonic anhydrase 2 deficiency, CSF-1 signalling abnormalities, chloride channel mutations
  • Thick sclerotic bone, bone laid down but no remodelled, in time bone marrow replaced by bone and haemopoiesis compromised
28
Q

What is Hyperparathyroidism?

A

Increase in circulating levels of PTH as a result of excess production by one or more parathyroid glands
Increases serum calcium levels
-Primary= intrinsic abnormality pf the parathyroid glands: adenoma (pathological increase in PTH production)
-Secondary= abnormality of calcium homeostatic: chronic renal disease (results in physiological hyperplasia)

29
Q

How is PTH related to Hyperparathyroidism?

A
  • Increases bone resorption= PTH acts on OBlasts to produce RANKL and decrease Osteoprotegerin with activation of OClasts
  • Increases renal Ca2+ resorption and phosphate loss
  • Enhances 25OH VitD conversion to 1,25(OH)2 VitD= increased Ca2+ uptake from GI tract
30
Q

What are the bone effects of Hyperparathyroidism?

A

Increased bone turnover

  • Increased osteoclastic activity (cortical thinning/ subperiosteal bone erosion)
  • Increased osteoblastic activity
  • Fragile bones that easily fracture (osteoporosis)
31
Q

What are the symptoms and signs of Hyperparathyroidism?

A
  • Bone and joint pain
  • Kidney stones, Excessive urination
  • Abdominal pain
  • TATT (tired all the time)
  • Depression or forgetfulness
  • Frequent complaints of illness with no apparent cause
  • Nausea, vomiting or loss of appetite
32
Q

What is Vitamin D and what does it do?

A

Most active form 1,25(OH)2 VitD (calcitriol) acts via VD Receptors- present throughout the body
Maintains serum calcium levels
-Increases calcium absorption from GI tract and kidney
-Increases bone resorption by increasing Oclast formation
Maintains serum phosphate levels
-Decreases PTH synthesis
-Increases FGF23 production

33
Q

What are the disorders of vitamin D metabolism?

A

Vitamin D deficiency
-Rickets
-Osteomalacia
Vitamin D resistance
-Vitamin D-dependent rickets type 2 (receptor mutation)
Lack of sunlight, dietary, GI malabsorption, liver disease, kidney disease

34
Q

What is the result of Vitamin Disease Deficiency?

A
  • Decreased serum calcium levels
  • Decreased serum phosphate levels
  • Effects directly via VD receptors and through hypocalcaemia
35
Q

What are the bone effects of vitamin D deficiency?

A

Mainly due to abnormal mineralisation

  • Osteomalacia= decreased mineralisation of bone
  • Rickets= decreased Ca2+/ Vit D in childhood, soft bones that deform and fracture easily
  • Serum calcium decreased= decreased phosphate and alkaline phosphate
36
Q

What is FGF23?

A

FGF23 levels regulated by serum PO4

  • Increased serum PO4 leads to increased production of FGF23 from osteocytes
  • Results in decreased production of PTH and 1a,25(OH)2D3
  • Increased PO4 loss in urine
  • Restoration of PO4 serum levels
37
Q

What diseases result from FGF23 over-production?

A

Autosomal dominant hypophosphatemic rickets

Phosphaturic mesenchymal tumour

38
Q

What is autosomal dominant hypophosphatemic rickets?

A
  • Mutation in FGF23 gene results in resistance to proteolysis
  • Low serum phosphate, renal phosphate wasting low a,25-dihydoxy Vitamin D3
39
Q

What is Phosphaturic mesenchymal tumour?

A
  • Rare soft tissue tumour that produces excess FGF23
  • Low serum phosphate, renal phosphate wasting, low 1,25-dihydoxy Vitamin D3
  • Decreased bone mineralisation with osteomalacia
  • Excision of the tumour is curative with reversal of clinical and laboratory abnormalities
40
Q

What disease is a result of abnormal FGF23 receptor signalling?

A

Hyperphosphatemic familial tumoral calcinosis

  • Loss of function mutations in FGF23 (or the FGF23 co-receptor a-Klotho)
  • Increased levels of phosphate in the blood (hyperphosphatemia)
  • Abnormal deposits of phosphate and calcium (calcinosis) in tissues

Locomotor (20 decks)

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