Bone Function, Structure and Development 2 Flashcards
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
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)
What does the basic multicellular unit consist of?
- Osteoclasts
- Osteoblasts
- Osteocytes
- Bone lining cells
- Blood vessel endothelium
What are the phases of the bone remodelling cycle?
- Activation
- Resorption (6 weeks)
- Reversal (1.5 weeks)
- Formation/ Mineralisation (5 months)
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
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)
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
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
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
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
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
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
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
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
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
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’
What are the chemicals involved in bone remodelling and mineralisation?
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?
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?
- 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?
- 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
- 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?
Achieved by young adulthood
- Genetic factors
- Physical activity
- Muscle strength
- Diet: calcium intake during adolescence
- Hormonal state
How is Osteoporosis linked to bone mass?
- 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?
- 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
