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05 - February 5, 2013.docx

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OSTEOIMMUNOLOGY Bone remodelling Osteoblast Osteoclast – bone eating cell The two balance how much bone we have Most diseases associated with bone loss – osteoclast start nibbling away at bone Control mice – overexpressing OPG – these transgenic mice had more bone mass OPG – What is the ligand to OPG? This is called RANK ligand – this protein given to _____ - becomes osteoclast, can see nibbling away at bone T cell – dendritic interactions RNAK ligand – is TNF superfamily molecule – binds to RANK on DC OPG – molecular decoy that looks like RANK – cannot signal, so decoy receptor – OPGL – called different names by different groups Can be cleaved so can be soluble RNAKL mutant mice – smaller, resemble hamster head, no teeth X-ray – in knockout, bone was shorter, completely solid – no bone marrow cavity Osteoclasts – stained in red in wild0type In knockout mice, no osteoclast The essential molecule in vivo that tells the progenitors in the hematoogenic lineage to become osteoclast No RNAK, no osteoclast The first experiment to prove that RNAK ligand is master regulator Molecular unit – myeloid progenitor gets survival signal – Less osteoclast, more bone – bones are turned over every ten years – Lots of effectors None of them can work if RANK or RANK ligand can work Osteoporosis – cannot escape it – women get it earlier; women have much less estrogen, which turns on the molecular decoy; after menopause, less estrogen, less molecular decoy, osteoclasts increase; sex bias; testosterone also controls this in men, but male physiology lasts ten, fifteen years more, so get osteoporosis Castrate a man, bone loss follows SEX HORMONES Control the bone pathway – why is because of the decoy Pathway Maybe T cells can change how much bone have in the body? Does the blood system affect how much bone we have? First experiment – activate T cell, make RNAK ligand, fix, and see osteoclasts Arthritis – could not jump Circles are osteoclasts Teeth loss – Develop diabetic model in mice – When block RNAK ligand, can block tooth loss Inflammatory cells make inflammatory cytokines – turn on locally production of RNAK ligand – inflammatory cells by themselves make RNAK ligand – if happen in joint, lots of RNAK ligand, osteoclasts nibble at the bones, leading to crippling and in periodontisis, tooth loss SEX HORMON Arthritis leads to bone loss, crippling Crohn’s disease – have severe bone loss – activated immune system – the cell type that really produce RANK ligand Thelper 17 cells – Leukemia – all leukemia cells make RNAK ligand Asthma – cortisone is the one of the best inducers of RNAK ligand; normally it shuts down immune system; but when exposed to T cells, makes RNAK ligands AIDS – chronic disease – Space flights Orthopedic implants – certain materials turn on RANK ligands, others don’t FREEDOM trial – Two injections of this antibody monoclonal against RANK ligand – reduced by 70% - approved Treatment of osteoporosis, skeletal events in cancer (metastasis in bone) Turning on osteoclasts – severe pain in metastasis – acidification of bone, nerve endings RANKL mutant mice – females could get pregnant, but none of the babies survived Babies never had milk in their stomachs – relation to milk production Progesterone receptors (PR) kick in – during pregnancy to proliferation signal Lactacting – RANK ligand – in the memory epithelium – RANK ligand in pregnant females – Early pregnancy, no RANK ligand Put in progresterone in pregantn female, turn on RANK ligand ?????? When rank ligand is knocked out, changes in puberty in mammary tissue does not occur When females get pregnant in knock out, complete block of proliferation of mammary tissue At end of pregnancy, normal females produce female In rank ligand knockout – complete block of lactacting ligands so babies die Essential function of system is to be turned on by sex hormones and pregnancy hormones to form lactacting mammory gland in mammals Osteoclast relase calcium from bone of mother – for the baby??? Function in pregnancy to suck up calcium from mother to give to baby – and at the same time, sets the tissue that nurtures the baby The sex hormone that did it is progesterone Inflammatory cells make RNAK ligand – binds to rank – by I kappa kappp kinases – cannot proliferate Sex hormone called progesterone turns on RANK ligand, which turns on proflieration of mammaory epitheilium –> breast cancer 70, 60% of deaths due to breast cancer have metastasis in bone Why does breast cancer like to go into the bone? If have osteoclast – If RANK ligand in breast and bone and tells tumour cells to g
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