Microsoft word - lecture 13-ca-reg hormones.doc

Intro to Endocrinology BSC 345, Lecture 13, Dr. David Rubin Calcium & Phosphate-Regulating Hormones: Chapter 9
I. Endocrine Physiology of Somatic Growth and Bone Growth GHRH, GHIH (Somatostatin), GH, IGF-1 (= Somatomedin C)Ca2+-Regulating Hormones: PTH, Calcitonin (CT) , Vit D3 (Calcitriol),Phosphate-Regulating Hormones: Phosphatonin and Stanniocalcin Parathyroid GlandBoneKidneyGutLiverSkin (Epidermis and Dermis) C. Flow Chart of GH secretion and regulation Somatostatin ⇒ Inhibition of GH secretionGHRH ⇒ Stimulation of GH secretion1. Direct Actions (Anti-insulin diabetogenic actions) a. Adipocytes (Fat Cells) ⇒ Lipolysis, ⇑ [serum lipids]b. Liver and Muscle ⇒ Gluconeogenesis, ⇑ [serum glucose] c. Pancreas ⇒ ⇑ insulin secretiond. To increase 1/2 life GH is bound to a GH binding protein a. Muscle ⇒ ⇑ Protein Synthesisb. Fat Cells ⇒ ⇑ Lipolysisc. Bone Chondrocytes ⇒ ⇑ Bone Growth and Cartilage Synthesis ⇓ [serum Glucose] ⇒ ⇑ GH secretion (opposes insulin) a. Laron Dwarfism
i. Abnormal underdevelopment of the body caused by insensitivity of the liver to GH secretion which results in a ⇓ IGF secretion.
ii. Normal [plasma GH] but little or none [plasma IGF] Intro to Endocrinology BSC 345, Lecture 13, Dr. David Rubin b. Primary Pituitary Dwarfism
Production of a defective GH molecule or insufficient GH amounts c. Hypothalamic Dwarfism
No GH is released because no GHRH is produced Acromegaly in adults or Gigantism in children
Enlargement of the bones of the head and extremeties due to excess GH secretion
II. Bone Growth and Ca2+/PO4 Metabolism
A. Long-Bone Growth (Fig. 9-2 & Table 9-3)
1. Bone is a metabolically active tissue composed of cells and extracellular matrix.
2. Bone is derived from mesenchymal cells which have further differentiated.
3. Principal Cells are: Chondrocytes: secrete cartilage matrix
Osteoblasts: bone forming cells
Osteoclasts: multinucleated giant cells responsible for bone formation and
Osteocytes: Osteoblasts which are trapped in a mineralized matrix.
4. Endochondral ossification is the ossification of cartilage at the Epiphyseal plate which contains the hypertropic chondrocytes. Avascular
5. Osteoblasts lay down the bone matrix on top of the chondrocytes. Vascularized
6. Bone is in a constant Flux of growth and remodeling from Osteoblast & Osteoclast
7. Cortical bone is densely packed columns of mineralized collagen laid down in layers
and is the major component of tubular bones (long bones).
8. Trabecular bone (cancellous bone) is spongy in appearance which provides strength
and elasticity in the axial (vertebral) skeleton.
9. Bone Matrix Proteins include: Osteopontin, Osteonectin, and Osteocalcin: Major extracellular protein of bone made by the osteoblasts
B. Regulation of serum Ca2+ and PO4 levels 1. Serum Ca2+ exists in three forms, Free (ionized), complexed (chelated), & protein 2. The ionized form of Ca2+ is the actively exchanged form which is sensed and 3. Ca2+ is essential for bone structure, intracellular fusion of secretory products, muscle function, neuron function, and 2nd messenger activation.
4. PO4 levels are not as tightly regulated, however, the biological roles of PO4 are of essential importance since they are necessary for ATP, DNA, proteins, andenzymes. PO4 is partitioned into three pools: kidney ultrafiltrate, bone, andintracellular soft tissue compartments.
5. Major site for PO4 excretion is the kidney, while Ca2+ excretion predominates in the feces. Factors (Fig. 9-1)
Intro to Endocrinology BSC 345, Lecture 13, Dr. David Rubin 6. Urinary excretion of Ca2+ is stimulated by PO4 deprivation, acidosis, adrenal steroids, and Na+ diuresis. Increase in urinary excretion may arise from a ⇓ renalreabsorption, ⇑ GFR, or both.
7. Intestinal absorption of PO4 is inhibited by ⇑ dietary Ca2+ levels.
C. Flow Chart of PTH, CT, and Vit D3 regulation of Ca2+ and PO4 1. Parathyrioid Glands (Fig. 9-1)
a. Four Parathyroid Glands (which are embedded in the Thyroid Gland) secrete Parathyroid Hormone (PTH). They are derived from embryonic
endoderm from the 3rd and 4th pharyngeal pouches. PTH is found in
ALL bony vertebrates (Chondrichthyes ?).
b. Prepro-PTH is synthesized in the Chief cells of the parathyroid gland. The endogenous form of circulating human PTH is 1-84, functionally 1-34 is
necessary for PTH type-1 receptor (PTH1R) binding and activation.
(Fig. 1-11*)
c. Ca2+-sensing receptors on the membranes of the parathyroid hormone cells
d. Membrane-spanning PTH receptors are in Bone (osteoblast cells, not e. ⇓ ionized serum Ca2+ ⇒ ⇑ serum PTH to conserve serum Ca2+ to promote:
i. Ca2+ mobilization from boneii. PTH enhances renal and gut absorption of Ca2+iii. PTH indirectly increases intestinal absorption of Ca2+ i. ⇑ rate of conversion of 25(OH)D3 to 1α,25(OH)2D3ii. ⇑ plasma Ca2+ concentrationsiii. ⇑ osteoclastic and osteoblastic bone resorption and remodelingiv. ⇑ urinary excretion of PO4 and ⇓ urinary excretion of Ca2+ 2. Parathyroid Hormone-related Protein (PTHrP) (Fig. 9-3)
a. Although PTHrP is a 141 amino acid protein, the N-terminal sequence of PTHrP has a significant homology to the N-terminal of PTH.
b. PTHrP is a paracrine hormone involved in bone and cartilage pattern formation during development (Chondrogenesis), as well as the
patterning of other tissues (skin, teeth, and pancreas).
c. PTHrP also binds to the common PTH1R with equal affinity as PTH
d. PTHrP can be produced by tumors ⇒ Humoral Hypercalcemia of
Malignancy (HHM) is the result do to very high levels of serum Ca2+.
Treatment is either calcitonin administration or remove the tumor
expressing the PTHrP.
3. TIP39 (tuberoinfundibular peptide of 39 residues) a. Newly isolated and characterized peptide with unkown functions.
b. Binds and activates the parathyroid hormone type-2 receptor (PTH2R).
c. Although TIP39 prefers to bind and activate the PTH2R, modified agonists
can be synthesized, such as 7-39TIP39, which can act as competitiveagonists to the PTH1R.
Intro to Endocrinology BSC 345, Lecture 13, Dr. David Rubin 4. Calcitonin (CT) is synthesized in the Thyroid Parafolicular cells (C cells)
a. Embryologically, the Parafolicular cells are derived from neural crest cells. In non-mammalian vertebrates, CT-secreting cells are localized in the
Ultimobranchial body which persists as a separate gland in all jawed
vertebrates except mammals.
b. CT is a proteolytically cleaved PreProhormone which gives rise to CT and Calcitonin gene-related peptide (CGRP, is produced in the brain)
c. CT receptors are in Bone and Kidney and have effects in opposition to PTHd. ⇑ serum Ca2+ ⇒ ⇑ [serum CT] ⇒ ⇓ serum Ca2+ & ⇓ serum PO4 e. ⇑ Renal Ca2+ and PO4 excretionf. No feedback inhibition directly on PTH secreting cellsg. Prevents Hypercalcemiah. Summary of Calcitonin effects: i. Protection against hypercalcemiaii. Blocking the actions of PTH in mobilizing bone Ca2+ & PO4iii. Stimulation of urinary excretion of both Ca2+ & PO4 5. Vitamin D (Steroid molecule, Cholecalciferol; Calcitriol; 1α,25(OH)2D3) a. Vit-D3 production is regulated at the kidney by PTH modulation of b. ⇓ serum Ca2+ ⇒ ⇑ serum Vit-D3 to conserve serum Ca2+ from kidney & gutc. Increases Gut absorption of Ca2+ and decreases Renal excretion of Ca2+ D. Flow chart of Vit D3 Synthesis (Figs. 9-5, 9-6, and 9-8* KNOW)
Dehydrocholesterol ⇒ Previtamin D3 ⇒ D3 ⇒ 25(OH)D3 ⇒ 1α,25(OH)2D3 from liver 2. 1α,25(OH)2D3 interacts with its nuclear Vitamin D receptor (VDR) to generate
biological responses involving signal transduction and nuclear transcription
modulation. (Fig. 9-10 & 9-11)
3. There are three VitD3-induced Ca2+-binding proteins produced as a result of activation of the VDR in target tissues.
a .& b. are Calbindins and belong to a family of tight Ca2+-binding proteins
c. Osteocalcin (= bone Gla protein, due to lots of γ-carboxyglutamic acid
residues) is an extracellular protein which binds Ca2+ Intestine: stimulate the absorption of dieatary Ca2+ and PO4 Bone: promote mineralization of bone matrix & stimulate bone resorptionKidney: reduce the urinary excretion of Ca2+ and PO4 Rickets:
Disease of children when bones do not harden and become malformeddue to an insufficiency of Ca2+ Intro to Endocrinology BSC 345, Lecture 13, Dr. David Rubin E. Bone Remodeling (Fig. 9-14 & Table 9-6)
1. Osteoclast and Osteoblast differentiation from different Mesenchymal stem cell lines2. These cells modulate the effects of PTH & CT on Bone Resorption & 3. Activators of Bone resorption and osteoclast* activation (via modulation of osteoblasts) are PTH and VitD3 BECAUSE *the osteoclast does not havereceptors for these hormones.
4. Bone Mineralization is mediated by CT via osteoclast Deactivation which causes a decrease in bone resorption. In addition,PTH enhances the production of VitD3 which is a major stimulator collagen,osteocalcin, and other matrix proteins Hyperparathyroidism ⇑ PTH secretion may cause several diseases
Osteoporosis ⇑ Ca2+ leaching from bone, brittle bones
Hypercalcemia ⇑ serum Ca2+
Hyperphosphatemia ⇑ serum PO4
Paget's Disease
Presentation: Familial, common in England and Northern European countries Characterized by he presence of excessive numbers of osteoclastsand osteoblasts which leads to structurally weakened bones.
Treatment: CT (Miacalcin) which stimulates the secretion of β-endorphine and reduces the pain associated with excessive bone turnover, andCT inhibits bone resorption.
Hypoparathyroidism
Due to damage or removal of PTH secreting glands,Female children predominate (2:1 females to males)Presentation: Hypocalcemia, Low serum PTH, Pseudohypoparathyroidism ⇓ serum Ca2+ & ⇑ PO4 with ⇑ PTH, also mental
deficiency, shortness of metacarpals (short 4th and 5th fingers), and a round face.
Possible ectopic calcification of muscle and brain tissue. Resistance to PTHadministration is due to faulty G-coupled proteins on the PTH receptors inbone and kidney. Therapy is to administer Ca2+ and VitD3.
Osteomalacia (Fig. 9-16 & 9-17)
Failure of normal mineralization of bone in adults (children = rickets) resulting inretardation of growth & skeletal deformaties. Due to diverse causes, but usuallyassociated with either a decrease inVitD3-responsiveness or VitD3-resistance.
1. VitD3 and Ca2+2. Calcitonin (Miacalcin nasal spray, = salmon calcitonin)3. Bisphosphonates (Phosamax, Risedronate, etc)4. Intermittent doses of PTH5. Estrogen receptor modulators (decrease bone resorption, raloxifen) Intro to Endocrinology BSC 345, Lecture 13, Dr. David Rubin 1. First identified in teleost fishes and produced from the corpuscles of Stannius cells.
2. Plays a major role in calcium/phosphate homeostasis in fish3. STC1, a mammalian homologue of stanniocalcin, has been shown that it is expressed in a time- and cell-specific manner and may play anautocrine/paracrine role during osteoblast development and bone formation(J Histochem Cytochem 2002 Apr;50(4):483-92. Stanniocalcin 1 (STC1) protein andmRNA are developmentally regulated during embryonic mouse osteogenesis: thepotential of stc1 as an autocrine/paracrine factor for osteoblast development and boneformation.) 1. The phosphatonins are a growing family of substances that act on multiple organs in autocrine, paracrine, and endocrine modes to regulate phosphate metabolism 2. Using three human diseases as models, fibroblast growth factor 23 and frizzled-
related protein 4 were shown to be associated with one or more of these
diseases.(Phosphatonins: a new class of phosphate-regulating proteins, CURRENT
OPINION IN NEPHROLOGY AND HYPERTENSION 2002;11:423-430)
3. FGF23 plays important roles in the development of hypophosphatemic diseases.
These findings will contribute to the development of new diagnostic andtherapeutic maneuvers for hypophosphatemic diseases. (Fibroblast growthfactor-23 is the phosphaturic factor intumor-induced osteomalacia and may bephosphatonin, CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION

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