BONE REMODELLING. Tim Arnett. University College London. Department of Anatomy and Developmental Biology

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1 BONE REMODELLING Tim Arnett Department of Anatomy and Developmental Biology University College London

2 The skeleton, out of sight and often out of mind, is a formidable mass of tissue occupying about 9% of the body by bulk and no less than 17% by weight. The stability and immutability of dry bones and their persistence over the centuries, and even millions of years after the soft tissues have turned to dust, gives us a false idea of bone during life. Its fixity after death is in sharp contrast to its ceaseless activity during life. Cooke AM 1955 Osteoporosis Lancet i: &

3 Ichthyosaur vertebral body Jurassic (~180 M yr)

4 Ichthyosaur Jurassic (~180 M yr)

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6 osteoclasts resorbing bone osteocytes entombed in bone osteoblasts forming bone

7 Two types of bone Woven (immature, fracture) large, rounded osteocytes osteocytes irregularly spaced randomly oriented collagen fibres variable collagen fibre diameter rapid matrix mineralisation forms rapidly rapid turnover Lamellar (mature, adult) smaller, flattened osteocytes osteocytes regularly spaced collagen fibres show regular, plywood orientation regular collagen fibre diameter delayed matrix mineralisation (few days) forms slowly slow turnover

8 Requirement for resorption during bone growth

9 Bone remodelling / turnover growth alterered mechanical requirements damage (macro / micro fractures) maintenance (failure prevention) calcium deficit senescence pathological (hyperparathyroidism, cancers, acidosis )

10 Healthy bone is highly vascular Bone gets about 7-8% of cardiac output Blood supply allows greater cellularity than in cartilage Enables remodelling and repair Bone also innervated (nerve fibres mainly associated with blood vessels) Contrast with cartilage (primitive, avascular)

11 Gray s Anatomy, Ed. 38

12 Alberts et al Molecular Biology of the Cell, Ed. 3

13 Remodelling animations (normal) download from Anat3048 website

14 Bone remodelling cycle

15 Osteonal (Haversian) systems in human cortical bone

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18 Adult human finger bone Key 1 = articular cartilage 2 = cortical bone 3 = trabecular bone 4 = marrow 5 = tendon

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20 Sub-periosteal bone remodelling

21 Osteoclast in resorption cavity

22 Bone remodelling balance formation > resorption growth formation = resorption steady state (adult ~20 45 yr) formation < resorption bone loss (= osteoporosis)

23 Bone turnover rates trabecular bone: ~25% / year cortical bone: ~2-3% / year lifespan of osteon in human cortical bone = ~15 years

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25 Collapsed third lumbar vertebra from 71 year old female showing osteoporotic trabeculae and collagenous scar tissue

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27 Remodelling animations (osteoporosis) download from Anat3048 website

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29 Low-power scanning electron microscope image of normal bone architecture in the 3 rd lumbar vertebra of a 30 year old woman marrow and other cells have been removed to reveal thick, interconnected plates of bone

30 Low-power scanning electron microscope image of osteoporotic bone architecture in the 3 rd lumbar vertebra of a 71 year old woman marrow and other cells have been removed to reveal eroded, fragile rods of bone

31 Detail of a trabcular bone element eroded by osteoclasts note extensive pitting and fragility

32 Detail of a trabcular bone element perforated by osteoclast action note pitting of the bone stalagmite

33 Low-power scanning electron microscope image of osteoporotic bone architecture in the 3 rd lumbar vertebra of a 71 year old woman marrow and other cells have been removed to reveal eroded, fragile rods of bone

34 Detail of trabcular bone eroded by osteoclasts note extensive pitting

35 Dual energy X-ray absorptiometry (DEXA)

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39 Contact-dependent Cell signalling Paracrine Signalling cell Signalling cell Target cell local mediator Target cells membrane-bound signal Endocrine Neuronal Endocrine cell blood vessel hormone Neurone cell body axon synapse neurotransmitter Target cell Target cell

40 Bone cell regulation Calcium-regulating hormones Parathyroid hormone (PTH) plasma Ca 2+ (critical regulator); OC recruitment, activity OB proliferation, activity; ie, bone turnover 1,25-dihydroxyvitamin D gut Ca 2+ uptake, plasma Ca 2+ ; OC recruitment, activity OB proliferation, OB (and skin cell) differentiation required for normal matrix mineralisation deficiency osteomalacia, rickets Calcitonin plasma Ca 2+ in young / hypercalcaemic animals OC recruitment, activity "emergency" hormone, not much effect in normal adults

41 Bone cell regulation Glucocorticoids (ie, - cortisol, cortisone, etc) necessary for normal bone development / function but in excess cause bone loss / osteoporosis Growth hormone required for normal bone growth Sex steroids (oestrogens & androgens) exert critical long term (ie slow acting) beneficial effects on bone maintenance OC recruitment, activity;? OB activity deficiency bone turnover, osteoporosis

42 Prostaglandins Bone cell regulation normal OB product; OB and OC activity mediate some actions of growth factors + cytokines & responses to mechanical stimuli Growth factors mitogens eg transforming growth factor ß, bone morphogenetic proteins, insulin-like growth factors I &II, platelet-derived growth factor, fibroblast growth factors normal OB products, deposited in bone matrix, often in large amounts may mediate some hormone actions Cytokines normal products of immune cells & also bone cells eg, - interleukins-1,2,3,4,6,10,11,13; tumour necrosis factor, RANK ligand (the major factor required for OC formation); colony-stimulating factors (esp. M-CSF1) mainly OC recruitment, activity - ie, cause bone loss some interleukins may mediate PTH, 1,25(OH) 2 vitamin D actions sex steroids may inhibit production of some interleukins

43 Bone cell regulation Inorganic agents protons (low ph; acidity) OC activity; mineralisation hypoxia (low oxygen tension) OC recruitment; bone formation phosphate OC recruitment, activity pyrophosphate mineralisation calcium OC recruitment, activity (small effect) fluoride bone formation (but bone is low quality) Mechanical loading v. important!

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