Bone Function, Structure and Development 2 Flashcards by Freya Millar

What is bone remodelling important for?

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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How often does bone remodelling take place?

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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What does the basic multicellular unit consist of?

Osteoclasts
Osteoblasts
Osteocytes
Bone lining cells
Blood vessel endothelium

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What are the phases of the bone remodelling cycle?

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

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What chemicals are involved in the regulation of bone remodelling?

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

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Describe the activation phase of the bone remodelling cycle

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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What are RANK interactions?

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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Describe the resorption phase of the bone remodelling cycle

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

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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Describe the reversal phase of the bone remodelling cycle

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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What are the roles for osteoclasts?

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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Describe the formation phase of bone remodelling

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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Describe bone mineralisation

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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How are matrix vesicles involved in bone mineralisation?

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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Describe local regulation of bone mineralisation

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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Describe systemic regulation of bone mineralisation

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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What are the chemicals involved in bone remodelling and mineralisation?

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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)

What are the types of Metabolic Bone Diseases?

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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

What is Osteoporosis?

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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

What does Osteoporosis result from?

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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

Describe the age related changes in bone mass

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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

What is peak bone mass determined by?

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Achieved by young adulthood

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

How is Osteoporosis linked to bone mass?

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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

What is Osteoporotic bone?

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Thinner cortical bone
Trabecular bone- struts thinner and less connected
Mechanically weak
Normally mineralised

What is Paget's Disease of Bone?

- 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

How is Paget's Disease genetically linked?

- 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)

What is Osteopetrosis?

- 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

What is Hyperparathyroidism?

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)

How is PTH related to Hyperparathyroidism?

- 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

What are the bone effects of Hyperparathyroidism?

Increased bone turnover - Increased osteoclastic activity (cortical thinning/ subperiosteal bone erosion) - Increased osteoblastic activity - Fragile bones that easily fracture (osteoporosis)

What are the symptoms and signs of Hyperparathyroidism?

- 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

What is Vitamin D and what does it do?

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

What are the disorders of vitamin D metabolism?

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

What is the result of Vitamin Disease Deficiency?

- Decreased serum calcium levels - Decreased serum phosphate levels - Effects directly via VD receptors and through hypocalcaemia

What are the bone effects of vitamin D deficiency?

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

What is FGF23?

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

What diseases result from FGF23 over-production?

Autosomal dominant hypophosphatemic rickets | Phosphaturic mesenchymal tumour

What is autosomal dominant hypophosphatemic rickets?

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

What is Phosphaturic mesenchymal tumour?

- 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

What disease is a result of abnormal FGF23 receptor signalling?

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

Bone Function, Structure and Development 2 Flashcards

(40 cards)