Pathology of Bone

summary of the lecture: it is a metabolic tissue that changes over time what type of tissue is bone? Mechanical: support + muscle attachments what are the 3 functions of the skeleton? Protective: vital organs + marrow Metabolic: ion homeostasis (particularly Ca2+ + PO4^3-) at what age does bone mass decrease? ~70 how long does it take for a big bone to renew itself? 8 years what tissue is bone formed from? specialised connective tissue what is bone made up of? extracellular matrix, which contains organic and inorganic components what proportion of bone is organic? 30% what are the organic components of bone? •collagen fibres •non-collagenous proteins essential to bone function what proportion of bone is inorganic? 70% what is the inorganic component of bone? hydroxyapatite crystals and other crystals of calcium + phosphate what are the 4 cells within bone? osteoclasts, osteoblast, bone lining cells and osteocytes bone resorption (break bone) what is the function of osteoclasts? bone formation (building) 1/8 what is the function of osteoblasts? what are bone lining cells? inactive osteoblasts involved in initiation of bone remodelling •mechanosensing •micro fracture repair •osteoblast differentiation what is the function of osteocytes? what is mechanosensing? (osteocytes) the ability to detect breakages and fractures within the bone bone cell types: histology if all bone was compact, we would not be able to move (since it heavy) why do we need spongy bone? compact bone cortical bone is a.k.a trabecular bone is a.k.a spongy bone 2/8 what are the 4 functions of the osteoblast? 1. forming the bone matrix 2. regulating mineralisation (calcification) 3. regulating osteoclast differentiation 4. precursors of bone lining cells and osteocytes what cells do osteoblasts differentiate from? stromal precursor cells what 2 transcription factors are expressed for osteoblast formation? RUNX2, Osx what is RUNX2 also known as? CBF-±-1 RunX2 and other transcription factors in order to become a committed osteoblast, what must be expressed? how is the differentiation of osteoblasts regulated? it is unknown how this occurs what are Hox genes? Hox genes encode transcription factors with a DNA-binding domain called a homeobox, and regulate development of the vertebrate body plan what signal is important for osteoblast commitment? BMPs = bone morphogenic proteins what hormones are involved in regulating osteoblast differentiation? PTH, vitamin D, glucocorticoids what protects committed osteoblasts from apoptosis? the release of intermittent PTH (it also regulates bone formation) 3/8 what do osteoclasts arise from? mononuclear cells osteoclasts develop from... bone marrow stem cells or (possibly) circulating monocytes bone resorption (breaking bone) calcium homeostasis what are the 2 functions of osteoclasts? what cell and what hormone do osteoclasts work with to establish calcium homeostasis? osteoblasts + PTH what are the 2 main signalling molecules responsible for osteoclast differentiation? OPG RANK-L OPG = osteoprotegerin what type of signalling molecule is RANK-L? it is a cytokine what proteins are expressed during osteoclast bone resorption? CTR, TRAP, Cathepsin K and H+/ATPase chemotaxis how do osteoclasts move to areas of micro-fracture? via integrin receptors 4/8 how do osteoclasts attach to the bone matrix? osteoclasts secrete acids and enzymes acidic environment removes mineral, enzymes remove proteins how is bone resorbed by osteoclasts? osteoclasts in vivo: how is signalling between osteoblasts and osteoclasts coordinated? RANKL/OPG system what is RANK and where is it found? RANK = cell surface receptor found on osteoclasts what cells express RANKL? osteoblasts and stroll cells what does RANKL binding to RANK result in? osteoclast differentiation + activation what does OPG act as? an inhibitory receptor - RANKL can bind to OPG instead of RANK, blocking signalling to osteoclasts summary diagram of RANKL/OPG system: if OPG is expressed too much, what hap- decreased bone resorption (breaking) > pens to bone? osteopetrosis if OPG is absent, what happens to bone? increased bone resorption > osteoporosis 5/8 if RANK-L is over-expressed, what hap- increased bone resorption > osteoporopens to bone? sis if RANK-L is absent, what happens to bone? decreased bone resorption > osteopetrosis if there is no RANK, what happens to bone? no bone resorption > osteopetrosis what is osteoporosis? fragility due to loss of bone density (breaking bone but not producing enough bone to replace it) what is osteopetrosis? very dense bone but fragile due to lack of repair (producing new bone w/out breaking old bone) factors that increase bone resorption increase the expression of what? RANK-L on osteoblasts what factors increase bone resorption? PTH, oestrogen deficiency, inflammatory cytokines, glucocorticoids what do osteocytes detect? microfractures what are osteocytes formed from? osteoblasts osteoblasts get trapped in the osteoid during bone ossification + mineralisation how do osteoblasts become osteocytes? •become integrated into osteocyte network what are the 2 functions of osteocytes? •regulate local mineralisation •initiate the bone remodelling cycle how is osteocyte behaviour regulated? •shear stress/damage •canalicular fluid flow the osteocyte network (diagram): 6/8 what is the bone remodelling cycle? how is bone resorption activated? osteocytes detect micro-fracture > this activates the bone > activates osteoblasts > activates osteoclasts > bone resorption what cells build bone? osteoblasts a group of bone cells that remove one structural unit (osteon) what is a bone remodelling unit? what leads to changes in the amount of an imbalance between bone resorption bone? and formation bone remodelling unit (histology): what is the periosteum? the tough membrane that covers the outside of the bone during growth, compare bone formation with resorption: bone formation > bone resorption what is the site of new bone growth during 'growth'/childhood? periosteal surfaces during adulthood, compare bone formation w/bone resorption: no net change in the amount of bone -repair of damaged bone takes place during ageing, compare bone formation w/bone resorption: resorption exceeds formation -net loss of bone from the skeleton what bone cell does oestrogen inhibit? inhibits osteoclast, so an oestrogen deficiency = ^ bone resorption what are SERMs? selective estrogen receptor modulators 7/8 how do SERMs work? selectively binding to oestrogen receptors, mimicking the effects of oestrogen and inhibiting bone resorption why is osteoporosis more common in menopausal women? menopausal women are deficient in oestrogen, oestrogen deficiency > bone resorption summary of factors affected bone balance: 8/8