709600
| Pregunta | Respuesta |
| Minerals involved in bone formation | Calcium, Phosphate, Magnesium |
| Regulators of Bone Formation | PTH, Vitamin D |
| What is extracellular calcium involved with? | -Excitation-Contraction coupling in the heart and muscles -Nervous System Function (synaptic transmission) -Exocytosis |
| What is intracellular calcium involved with? | -second messenger -Intracellular messenger -Muscle contraction |
| How is most Ca excreted? | most is excreted in the feces |
| Three forms of Calcium | -45% ionized (free or unbound) -45% bound (albumin) -10% complexed (to other small anions: phosphate, citrate, carbonate, oxalate) |
| Extracellular to intracellular calcium gradient | 10,000 fold gradient from outside to inside -->diffusion through channels |
| Phosphorus distribution in the body | -85% in the bone -14% in soft tissue (phospholipids, DNA/RNA, ATP) -1% in blood (inorganic phosphate) |
| How is Phosphorus excreted | Through the urine |
| Serum forms of Phosphorus | 50% ionized 10% Protein bound 40% Complexed |
| Distribution of Mg in the body | 65% in skeleton The rest is in soft tissues, usually as enzyme co-factor -Regulates neuromuscular excitability |
| Regulatory effects of Mg+ | Cardiac and Skeletal muscles |
| Which portion of the bones are targeted by androgens and why | Epiphyseal line |
| What is in the ECM? | -Hydroxyapetite Proteins (confers strength to the bone) Type 1 collagen -->tensile strength Osteocalcin -->Binds Ca+ and crystals (induced by Vit D) Osteonectin: Binds crystals and collagens |
| Cells involved in remodeling bone | Osteoblasts, Osteoclasts, Osteocytes |
| Cortical vs Trabecular Bone | 80% Cortical: Slow turnover, mechanical strength. ECM+ Minerals+ vessels + osteocytes 20% Trabecular: spicules of interconnected bone, fast turnover and Ca+ balance, site of metastasis (HIGHLY VASCULARIZED) |
| Components of the Osteon | Haversian Canal + Lamellae |
| Osteocytic Osteolysis | transfer of calcium from the interior of the growth surface through the canaliculi |
| Which cells secrete growth factors into the matrix? | Osteoblasts |
| What stimulates stem cells to become osteoclast precursors | M-CSF from the osteoblasts |
| How are osteoclasts activated? | IL-6 and RANK ligand secreted from osteoblasts |
| What is nucleation? | Process of Bone formation in the cortical region Ca+ and inorganic Phosphate come together to build layer of bone through osteoblasts |
| Progression of stem cell stimulation | Vit D causes osteoblasts to secrete M-CSF which causes stem cells to differentiate into osteoclast precursors. These mature into mononuclear osteoclasts. This matures into a (multinucleated) functional osteoclast |
| What condition is necessary to reabsorb calcium? | acidification by lysosomes break up the bone |
| What is the purpose of osteoprotegerin? | It sequesters the RANK ligand until resorption is favored OPG is sequestered itself til needed |
| RANK/OPG in metastasis | Tumors can secrete more RANK ligand and reduce OPG molecules allowing for mass resorption. Osteoclasts will outnumber osteoblasts |
| PTHrp | Parathyroid related hormone that can be secreted by tumors to upregulate osteoclast activity. Drops OPG and increases RANK |
| location of parathyroid gland? | 4 nodules on the back of the thyroid gland South of the pharynx and epiglottis |
| Why is the half life of PTH important? | Short half life (2-4 min) allows PTH and calcium to be tightly regulated on a moment to moment basis |
| Calcium regulation of PTH | When calcium is 1.1-1.3 mmol/L, PTH is released Extracellular calcium regulates synthesis and secretion of PTH |
| How does Vit D affect PTH | 1,25 (OH)-vitamin D translocates into the nucleus and binds with its nuclear receptor - Vit D Receptor (VDR). The VDR dimerizes with RXR and docks on the Vitamin D response element (VDRE), which blocks the PTH gene promotor |
| What regulates PTH production? | Low extracellular Ca+ stimulates PTH production (High Ca+ inhibits PTH) Low extracellular Mg+ stimulates PTH and high inhibits it. Prolonged low Mg+ inhibits PTH release Vit D (1,25) inhibits PTH |
| Why does low extracellular Mg+ inhibit PTH secretion? | Mg+ is also needed for exocytosis |
| What senses calcium steroid levels? | Calcium Sensing receptor (CaSR) on the Parathyroid hormones (located on back of thyroid) |
| CaSR activation | Ca+ binds to the 7 transmembrane GPCR on the surface of the parathyroid cells (chief cells) which leads to a conformational change G-alpha-q --> PLC --> IP3 + DAG --> Ca+ increase and PKC --> INHIBITION OF PTH SECRETION Decreases Pre-Pro-PTH transcription |
| Familial Hypercalcemic Hypocalcuria | Abnormality in the CaSR causes a sensitivity shift. Higher levels of Ca+ needed to inhibit PTH secretion. Perceived lack of Ca+ causes for more secretion of PTH High levels cause for excretion in the urine |
| PTH Receptor 1 (PTHR1) Where is it? Structure? Binds? | -7 transmembrane GPCR -Located on the Convulted Tubules and osteoblasts -Binds PTH and PTrH |
| PTH affect of inorganic phosphate. Why? | It inhibits resorption of inorganic phosphate. You don't want too much P- and Ca+ in the blood together simultaneously bc it will precipitate into a salt |
| Consequences of hypocalcemia? | Muscle stiffness, Contractures, cramps, decreased cardiac contractility, Hyperexcited nerves, anxiety, siezures, cardiac arrest 1.1 mM |
| Consequences of hypercalcemia? | Polyuria, constipation, Fatigue, Calcium deposits, cardiac arrhythmia 1.5 mM Only occurs if the jump from hypo to hyper happens quickly. Otherwise the body adapts and high becomes normal |
| Why does hypocalcemia lead to cardiac arrest? | Cardiac muscles rely on extracellular calcium to contract. If not enough extracellular Ca+, then you die Muscles rely on internal stores from the Sarcoplasmic reticulum so they'll be ok |
| Effects of PTH on renal tubules | -increase resorption of Ca+ - decrease phosphate resorption - increase Vit D (1,25) production |
| Effect of Calcemia | -Ca+ release from bone mineral -osteoblastic cell activity -bone matrix degradation |
| Effects of Phosphatemia | -renal cells convert 25-(OH)D to 1,25-(OH)D -intestines increase phosphate resorption -bone will release phosphate |
| Drug treat hyperparathyroidism | Calcimimetic It lowers PTH levels acts as a mimic of calcium |
| Drug treating osteoperosis | Calcilytic (CaSR antagonist) Increases PTH |
| Where does Vitamin D act? | Kidney, bones, intestine in order prevent abnormal flux in Ca+ levels |
| What stimulates 7-dehydrocholesterol to cholecalciferol and where? | UV light (in the skin) |
| What form of Vitamin D can you get from your diet? | Cholecalciferol |
| Which version of Vit D is seen as a reservoir and where is it from? | 25-hydroxycholecalciferol |
| What hormone turns 25-hydroxycholececaliferol to 1,25-(OH) | PTH (occurs in the kidney) |
| Which form of Vit D is more likely to bind to it's nuclear steroid receptor? | 1,25-(OH)d3 |
| Which form of Vitamin D is most biologically active? | (25-OH)D |
| What is the main regulatory step of Vitamin D production? | Conversion of 25(OH)D to 1,25(OH)D by the enzyme 1-alpha-hydroxylase in the kidney. PTH causes the activation of 1-a-hydrolase |
| What genes do Vitamin D upregulate? | Upregulate Calbindin |
| What does Calbindin do? | Calbindin sequesters calcium in the cell allowing for quick access while maintaining the huge gradient |
| Negative feedback of Vitamin D | 1,25(OH)D inhibits it's own production from 25(OH)D and the conversion of Cholecalciferol to 25(OH)D |
| Foods rich in Vitamin D | Eggs, Fish, Cod Liver Oil, Milk |
| Direct effect of Vit D in the bone | Increases osteoclasts to reabsorb bone, thus releasing Ca+ into the bloodstream |
| Indirect effect of Vitamin D on Bone | Provides Ca+ and P- for bone formation through its actions on the kidney |
| Net effect of Vit D | Indirect effects >>> Direct Effects More osteoblast activity and bone growth |
| Calcitonin produced by which cells? | Parafollicular Cells (C-cells) of the Thyroid Gland. |
| Type of receptor on C-Cells | CaSR |
| When is calcitonin released? | In response to high serum Ca+ levels |
| What is the function of Calcitonin? | Inhibit bone resorption -Helps in calcification (eggshells) |
| Therapeutic options for Osteoperosis | 1. Antiresorptives: Bisphosphonates (bind Ca+ to make hydroxyapetite which is deposited to bone), Estrogens, ER-modulators, Calcitonin, Densumab (Anti-RANK). 2. Anabolics: PTH, antisclerosin, Calcilytics |
| Intermittent PTH vs Sclerosin Inhibitors | Intermittent PTH allows for increased turnover but less efficient osteoblasts Sclerosin inhibitors allow for more pure formation and potent growth (less osteoclasts) |
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