Ca regulating hormones. Introduction

Transcription

1 Ca regulating hormones Introduction: effects of Ca / PO4 ions; Parathyroid: anatomy, histology, PTH; Thyroid: anatomy, histology, Calcitonin; Kidney: Vit D. Overview of Ca regulation: bone, kidney, and GI tract as effectors of Ca regulating hormones. 06 PTH: structure, receptor, secretion, effect of Ca / Vit D metabolites / other factors, effects Calcitonin: structure, biological actions, effect on osteoclasts and bone reabsorption Vit D: production and metabolism, absorption, transport and excretion, biological actions Diseases: hypopth, low Ca tetany, hyperpth, kidney stones, rickets, osteoporosis. Case study (e.g. hypocalciuric hypercalcemia) Introduction Hormones and story lines parathyroid gland + + PTH blood Ca - thyroid gland Vit.D Calcitonin + kidney Page 1

2 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Ca is required for Na permeability in nerves, Ach release at NMJ, excitation - contraction coupling in muscles, (e.g.. low ECF-Ca and tetany) Ca serves as intracellular signal for some hormones (e.g.. Epinephrine on stroke volume) Ca is needed for some enzymes effect, for the secretion of proteins, for blood clotting to occur (e.g.. EDTA) Ca is a constituent of bone (Ca storage depot) PO4 functions as part of intracellular buffer systems PO4 is an important constituent of macromolecules such as nucleic acids, phospholipids, metabolic intermediates, and phosphoproteins PO4 is a constituent of bone (PO4 storage depot) Why do blood Ca and PO4 levels are regulated??? Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Ca serves as intracellular signal excitable VGNaC VmCa VGCC SERCa IP3 Ry non-excitable G q ec fca entry icf TTX - sensitive TTX - non sensitive Tyr-K Gs Gi storage mito metab packaging exocytosis gene express.. cytoskeleton enzymes/r PKC PLC PLD IP3R RyR VGCC VGCCs, LVA vs HVA LVA, rapid and voltage inactivation HVA, slow inactivation T-,L-,N-,P-,Q, and R-type of VGCCs diversity due to multiple genes for Ca channel subunits and alternative splicing. The alpha1 subunit has the voltage sensor, gating machinery, and a channel pore. basal pacemaker activity, plasma membrane Ca oscillator, action potentials last longer ( ms) some NPs, Nts and hormones act by modulating spontaneous activity of the pituitary membrane oscillator Why do blood Ca and PO4 levels are regulated??? Page 2

3 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies What endocrine signals control all these calcium fluxes??? Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies PTH and Vit.D increase blood Ca while Calcitonin decreases it blood Ca decrease calcium receptor parathyroid gland PTH PTH receptor Gs / AC Gq / PLC intestine Vit. D absorption secretion Calcitonin filtration bone formation, osteoblast kidney, Ca filtration intestine, Ca secretion bone resorption, osteoclast kidney, Ca reabsorption, Vit. D intestine, Ca absorption blood Ca kidney PTH resorption formation Calcitonin reabsorption PTH What endocrine signals control all these calcium fluxes??? bone Calcitonin receptor Gs / AC Calcitonin thyroid gland calcium receptor blood Ca increas e Page 3

4 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies ECF ICF The Ca receptor is a 7 tm domain receptor with its large amino terminal domain in the extra cellular side of the plasma membrane Potential glycosylation sites are located in the extracellular domain Potential PKC phosphorylation sites are in the intracellular domain Hypercalcemia decreases camp and PTH release from parathyroid, while hypocalcemia increases both camp and PTH release Teophylline and camp stimulate PTH release Examples of pathologies: pseudo hypoparathyroidism type Ia (alpha subunit of Gs) and familial hypocalciuria hypercalcemia (Ca receptor) The Ca sensor is a seven transmembrane domain receptor Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies PTH is only made in the parathyroid gland and is essential for Ca homeostasis Page 4

5 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies PTH is made in the parathyroid only (84 aa). It is essential for Ca homeostasis PTH acts directly on the skeleton and kidneys PTH is the product of a single copy gene (pre-pro- PTH) PTH gene is subject to strong repressor activity in all cells but parathyroids PTH gene transcription is negatively regulated by ECF- Ca and by active Vit. D cis elements in PTH gene include Ca response element (CaRE), Vit. D response element (VDRE), and a camp response element (CRE) PTH is only made in the parathyroid gland and is essential for Ca homeostasis Introduction Parathyroid PTH on Ca absorption in distal nephron PTH on Ca absorption on proximal tubule Thyroid Vitamin D Bone turnover Pathologies PTH is only made in the parathyroid gland and is essential for Ca homeostasis Page 5

6 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies PTH R AC Gs Gq PLC ATP camp, PKA PI2 IP3, Ca rise DAG, PKC PTH is made in the parathyroid only (84 aa). It is essential for Ca homeostasis PTH acts directly on the skeleton and kidneys PTH is the product of a single copy gene (pre-pro- PTH) PTH gene is subject to strong repressor activity in all cells but parathyroids PTH gene transcription is negatively regulated by ECF- Ca and by active Vit. D cis elements in PTH gene include Ca response element (CaRE), Vit. D response element (VDRE), and a camp response element (CRE) PTH is only made in the parathyroid gland and is essential for Ca homeostasis Introduction Parathyroid Thyroid As Ca plasma content rises PTH secretion decreases Vitamin D Bone turnover PTH increases plasma Ca concentration Pathologies PTH secretion and plasma calcium concentration Page 6

7 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies PTH stimulates osteoclasic activity and Calcitonin inhibits it Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies PTH stimulates osteoclasic activity and Calcitonin inhibits it Page 7

8 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies PTH stimulates osteoclasic activity and Calcitonin inhibits it Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies A) B) C) Local osteolytic hypercalcemia secondary to leukemia Hypercalcemia of malignancy 2nd to squamous cell carcinoma Hyperparathyroidism. Note the abundant osteoclasts (large arrows), osteoblasts (small arrows) and osteoids PTH stimulates osteoclasic activity and Calcitonin inhibits it Page 8

9 Introduction Parathyroid Thyroid Vitamin D Bone turnover A hand radiograph in primary hyperparathyroidism. Note the subperiosteal erosions, which are more prominents along the radial border of the phalanges. Pathologies PTH stimulates osteoclasic activity and Calcitonin inhibits it Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies The mechanism of action elicited by PTH involves AC and PLC Page 9

10 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies The mechanism of action elicited by PTH involves AC and PLC Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Overall regulation of calcium balance by PTH Page 10

11 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Calcitonin Calcitonin is synthesized (32 aa peptide) by parafollicular or C cells of the thyroid gland its primary action is to inhibit bone resorption by inhibiting osteoclast lysosomal activity its gene encodes multiple mrna (CGRP) whose peptides ( and ß) cause arterial vasodilatation. CGRP is widely distributed in central & peripheral nervous system, heart, lungs, thyroid, & GI the main stimuli for Calcitonin secretion are an elevated serum Ca and the GI hormone gastrin its mechanism of action is through camp / PKA The mechanism of action elicited by calcitonin involves AC and camp Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Calcitonin Calcitonin is synthesized (32 aa peptide) by parafollicular or C cells of the thyroid gland its primary action is to inhibit bone resorption by inhibiting osteoclast lysosomal activity its gene encodes multiple mrna (CGRP) whose peptides ( and ß) cause arterial vasodilatation. CGRP is widely distributed in central & peripheral nervous system, heart, lungs, thyroid, & GI the main stimuli for Calcitonin secretion are an elevated serum Ca and the GI hormone gastrin its mechanism of action is through camp / PKA The mechanism of action elicited by calcitonin involves AC and camp Page 11

12 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Calcitonin is synthesized (32 aa peptide) by parafollicular or C cells of the thyroid gland its primary action is to inhibit bone resorption by inhibiting osteoclast lysosomal activity its gene encodes multiple mrna (CGRP) whose peptides ( and ß) cause arterial vasodilatation. CGRP is widely distributed in central & peripheral nervous system, heart, lungs, thyroid, & GI the main stimuli for Calcitonin secretion are an elevated serum Ca and the GI hormone gastrin its mechanism of action is through camp / PKA The mechanism of action elicited by calcitonin involves AC and camp Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies AC Gs R HCO3 - pump - Cl Calcitonin ATP camp - CO2 + H2O <---> <---> H2CO3 <---> + - <---> H HCO3 HCO3 - carbonic anhydrase Cl -+ H -> + HCl lysosome osteoclast lysosomal enzymes ruffled border Calcitonin is synthesized (32 aa peptide) by parafollicular or C cells of the thyroid gland its primary action is to inhibit bone resorption by inhibiting osteoclast lysosomal activity its gene encodes multiple mrna (CGRP) whose peptides ( and ß) cause arterial vasodilatation. CGRP is widely distributed in central & peripheral nervous system, heart, lungs, thyroid, & GI the main stimuli for Calcitonin secretion are an elevated serum Ca and the GI hormone gastrin calcified bone its mechanism of action is through camp / PKA The mechanism of action elicited by calcitonin involves AC and camp Page 12

13 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Calcitonin and CGRP, two different ways of processing the same gene Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies PTH Low PO4 Low Ca Estrogen Prolactin GH Placental lactogen - 1, 25 - Dihydroxy cholecalciferol ( 1, 25 - (OH)2 D3 ) hydroxy -latio n 7-Dehydro cholesterol (pro Vit. D) skin irradiation Cholecalciferol (Vit. D3) liver 25 - hydroxylation 25-Hydroxy cholecalciferol (25 - (OH) - D3) 24 - kidney hydroxylatio n 24, 25 - Dihydroxy cholecalciferol ( 24, 25 - (OH)2 D3 ) produced in kidney, acts on the intestine, bone, kidney, and the parathyroid gland (VDR, DNA) acts as steroids do in nuclei of target cells. Its main effect is to increase GI - Ca absorption inhibits PTH synthesis and secretion. Use in secondary hyperpth of chronic renal failure liver 25-hydroxylation is an obligatory step for binding to the Vit. D receptor (VDR). Highest activity occurs after kidney 1 -hydroxylation regulatory control is at a switching mechanism in kidney between 1 and 25 hydroxylase. Inputs are low PTH, Ca, PO4, and other hormones Vit.D is activated in the kidney by the action of PTH Page 13

14 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies skin liver kidney 1-25-hydroxycholecalciferol (active Vit D3) 7-dehydrocholesterol Vit.D is activated in the kidney by the action of PTH cholecalciferol (inactive Vit D3) 25-hydroxy- cholecalciferol (inactive Vit D3) (OH)2-D3 produced in kidney, acts on the intestine, bone, kidney, and the parathyroid gland (VDR, DNA) acts as steroids do in nuclei of target cells. Its main effect is to increase GI - Ca absorption inhibits PTH synthesis and secretion. Use in secondary hyperpth of chronic renal failure liver 25-hydroxylation is an obligatory step for binding to the Vit. D receptor (VDR). Highest activity occurs after kidney 1 -hydroxylation regulatory control is at a switching mechanism in kidney between 1 and 25 hydroxylase. Inputs are low PTH, Ca, PO4, and other hormones Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Vit.D is activated in the kidney by the action of PTH Page 14

15 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Vit.D activation is inhibited in the kidney by PO4 and in the parathyroid by Ca on PTH Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies (antagonistic effect of glucocorticoids at a genomic level) The mechanism of action of Vit.D is at the genomic level Page 15

16 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies The mechanism of action of Vit.D is at the genomic level Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies In its free state VDR receptor binds to its HRE as a heterodimer with retinoid-x. The carboxy-terminus of VDR interacts with TFIIB preventing the formation of a stable preinitiation complex and, together with a corepressor, silences transcription. Upon Vit. D binding, its receptor undergoes a conformational change, dissociation of the co-repressor, a decreased interaction of the VDR with the carboxy-terminus TFIIB and an increase interaction of the VDR aminoterminus with TFIIB. These changes facilitate TFIIB binding an assembly of a stable preinitiation complex, the binding of RNA polymerase II and the activation of transcription initiation. Antagonistic effect of glucocorticoids at a genomic level The mechanism of action of Vit.D is at the genomic level Page 16

17 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies The mechanism of action of Vit.D is at the genomic level Introduction Parathyroid Thyroid Right hip Lumbar spine Vitamin D Bone turnover osteoporosis osteoporosis Pathologies Radiographic appearance of osteoporosis in humans Page 17

18 Introduction Parathyroid Thyroid Vitamin D Bone turnover Adolescence Young adults After third decade Menopause Advance age Pathologies Radiographic appearance of osteoporosis in humans Introduction Parathyroid Thyroid The vertebra show decreased bone mineral density and some vertebra are clearly compressed. Vitamin D Bone turnover Pathologies Radiographic appearance of osteoporosis in humans Page 18

19 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies A model for the general control of bone turnover Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies hyperpth, primary or secondary, leads to altered function of bone cells, renal tubules, and GI mucosa (kidney stones, bone decalcification, bone fractures) secondary hyperpth occurs associated with low Ca due to chronic renal disease or to Vit. D deficiency hypopth due to inactivating mutations of the PTH gene, and due to activating mutations in the parathyroid Ca-sensing receptor have been reported Vit.D-dependent rickets: type I is due to an inherited defect in the renal 1a-hydroxylase gene and the type II (rare) is due to an inherited defect in the VDR leading to grossly elevated serum 1, 25 - (OH)2 VD3 Examples of calcium - related endocrine pathologies Page 19

20 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Osteomalacia (rickets) caused by simple nutritional Vit. D deficiency resulting from impaired mineralization of newly formed bone. Osteomalacia is the result of a lack of Vit. D, impairment of Vit. D metabolism, or lack of Ca or P at the mineralizing site. Before growth plate closure the same condition is referred as rickets and is characterized by failure of calcification of cartilage at the growth plate. Examples of calcium - related endocrine pathologies Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Osteomalacia (rickets) caused by hypophosphatemia. is also known as phosphate diabetes or Vit. D resistant rickets. Is associated with growth retardation and bowing deformities of the legs. Patients have normal serum Ca with low P content due to increase urine P excretion (phosphate depletion resulting from renal tubular dysfunction). Examples of calcium - related endocrine pathologies Page 20

21 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Paget s disease is characterized by marked focal increase in bone resorption and bone formation resulting in disorder bone architecture (e.g. bowing of the femur, bone destruction and soft tissue swelling). Viral origin?? Examples of calcium - related endocrine pathologies Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Paget s disease is characterized by marked focal increase in bone resorption and bone formation resulting in disorder bone architecture (e.g. bowing of the femur, bone destruction and soft tissue swelling). Viral origin?? Examples of calcium - related endocrine pathologies Page 21

22 Introduction Parathyroid Thyroid Vitamin D Bone turnover Pathologies Examples of calcium - related endocrine pathologies Page 22