Carnegie 4

Players of calcium homeostasis

• Calcitonin (during childhood)

• Parathyroid hormone (PTH)***

• Vitamin D

Target of calcium homeostasis

• GI tract

• Bone

• Kidneys

Goal of calcium homeostasis

Maintain blood calcium levels within a certain range, regardless of diet and bone density

99% of calcium in the body is stored where?

bone and teeth (majority in bone)

Hormones that increase bone deposition

• Insulin

• Growth hormone

• IGF-1

• Estrogen

• Testosterone

• Calcitonin (during childhood)

Hormones that increase bone resorption

• PTH

• Cortisol

• T3 and T4

Bone is seen as a ______ by the body

bank of calcium

Bone is constantly remodeled via the actions of ___________

osteoblasts and osteoclasts

Mechanical stress of bones also encourages ______

bone deposition

Calcium storage

• Of the 1% of calcium remaining (not in bones or teeth), 90% of it is inside cells, leaving only 0.1% of body calcium available in the ECF

• Of the 0.1% in ECF, half is bound to proteins or phosphate

Osteoblast

derived from bone marrow stromal cells and deposit calcium in bone

Osteocytes

retired osteoblasts and maintain bone tissue

Osteoclasts

derived from macrophages and digest bone to release calcium into the circulation

0.05% of total body calcium as _______

free calcium

Free calcium available for essential functions such as

• neuromuscular excitability (influences Na+ permeability)

• excitation-contraction coupling in cardiac and smooth muscle

• stimulus-secretion coupling

• maintenance of tight junctions

• blood clotting

absence of ___ is fatal within days due to lack of calcium to maintain stimulation of diaphragm contraction

PTH

Parathyroid hormone (PTH)

• Peptide hormone secreted in response to decreased blood calcium and will influence all 3 targets

  • Bone

  • GI tract

  • Kidney

Bone

stimulates resorption – fastest option to quickly raise blood calcium

GI tract

stimulates calcium absorption from diet (this is regulated)

Kidney

increases tubular calcium reabsorption to return it to bloodstream

Calcium is an excellent example of _________ of hormone release

Humoral regulation

Note that bone resorption moves both _________ and _______ into the bloodstream. This has the potential to be self defeating.

PTH deals with this by ______ excretion at the level of the kidneys so that the calcium remains as _______, available to various target cells.

• calcium and phosphate

• increasing phosphate

• free calcium

Humoral regulation of calcium

Balance between osteoblast products

Osteoblasts and their precursors → RANK ligand (RANKL) → Macrophages/ osteoclasts → (triggered by binding of RANKL and RANK) Differentiation of macrophages into osteoclasts and Suppression of osteoclast apoptosis → increase Osteoclast action → Osteoclast action outpaces osteoblast action → decrease Bone mass

Osteoblasts and their precursors → Osteoprotegerin (OPG) → RANKL bound to OPG not available to bind with RANK → Blocks action of RANK → decrease Osteoclast action → Osteoblast action outpaces osteoclast action → Bone mass

Estrogen can help maintain ________ by activating the gene responsible for _______

bone density

OPG production

RANK

Receptor Activator of NF-k B (nuclear factor kappa NF-Kß - found on macrophages and induces them to differentiate into osteoclasts)

PTH activates ________ to promote ________ from the GI tract: Vitamin D is considered to be acting as a hormone in this context'

Two hydroxylations are required to get the active form: 1,25-dihydroxyvitamin D

Vitamin D

calcium absorption

Calcitonin

• a minor player

• Secreted by thyroid parafollicular cells in response to elevated blood calcium

• Inhibits osteoclasts (maximize osteoblast (increase bone growth))

• Important during childhood growth

• Not a key player in the day-to-day regulation of bone density in adults

Osteoporosis

• Loss of matrix and minerals, especially in response to aging

• More common in women because decreasing levels of estrogen after menopause

Osteoporosis treatment

• anti-osteoclast drugs including calcitonin (nasal spray)

• SERMS (selective estrogen receptor modulators)

• newer drugs look at promoting osteoblasts rather than simply interfering with osteoclasts – possibly statins, also another type of estrogen signaling molecule

Bisphosphonates

• they incorporate into calcium at the bone matrix

• during resorption, they enter into the clasts by transcytosis

• they induce apoptosis of excess clasts

• they do not interfere in bone physicochemical properties

Adrenal glands

• paired, pyramid-shaped organs on top of kidneys (suprarenal glands)

• structurally & functionally, 2 distinct endocrine glands in one

  • adrenal medulla

  • adrenal cortex

adrenal medulla

nervous tissue forms core of gland; derived from neural crest and acts like part of sympathetic ns

adrenal cortex

encapsulates medulla & makes up most of glans; derived from mesoderm- 3 functional areas

3 functional areas of adrenal glands

• adrenal cortex

  • zona reticularis- sex steroids

  • zona fasciculata- glucocorticoids

  • zona glomerulosa- mineralcorticoids

• adrenal medulla- catecholamines

Adrenal medulla

• composed of chromaffin cells which are modified postganglionic neurons

• cells are clustered around capillaries; secrete E/NE (80/40) into ECS – then via blood stream to targets

Catecholamines

• derivatives of the amino acid tyrosine

• role is to prolong the body’s “fight or flight” response that was initiated by the SNS → constriction of blood vessels, increased blood sugar, faster heartbeat, diversion of blood to brain, heart & skeletal muscles

• sympathetic nervous system stimulates medullary release of catecholamines; fast-acting but brief responses to stress

Release of E/NE

Hypothalamus → spinal cord → sympathetic fibers to adrenal medulla → release of E (mostly) and NE

Short-term stress response (reinforces response initiated by SNS)

1. Increased heart rate

2. Increased blood pressure

3. Liver: glycogenolysis & release of glucose to blood

4. Dilation of bronchioles

5. Redirected blood flow → increased alertness, decreased digestive system activity, reduced urine output

6. Increased metabolic rate

α1 and β1 adrenergic receptors tend to exert effects that are _____

stimulatory

α2 and β2 adrenergic receptors tend to be _______

inhibitory

α1

Location: Most sympathetic target cells

Affinity catecholamine for NE and E: NE > E

Typical response elicited: Excitatory

Example of responses elicited: Generalized arteriolar vasoconstriction (increase smooth muscle contraction)

α2

Location: Digestive system

Affinity catecholamine for NE and E: NE < E

Typical response elicited: Inhibitory

Example of responses elicited: Decreased motility in digestive tract (tsmooth muscle contraction)

β1

Location: Heart

Affinity catecholamine for NE and E: NE = E

Typical response elicited: Excitatory

Example of responses elicited: Increased rate and strength of cardiac muscle contraction

β2

Location: Skeletal muscle; smooth muscle of some blood vessels and organs

Affinity catecholamine for NE and E: E only

Typical response elicited: Inhibitory

Example of responses elicited: Breakdown of glycogen in skeletal muscle; bronchiolar dilation and arteriolar vasodilation in skeletal muscle and heart (I smooth muscle contraction)

Steroidogenesis in the adrenal cortex

Aldosterone & cortisol are structurally very similar – consequence?

• increase levels for long periods

• can bind to other receptors

Reproductive Steroids pathway

Cholesterol → pregnenolone → DHEA

Glucocorticoids pathway

Cholesterol → progesterone → 17-OH-progesterone → cortisol

Mineralocorticoids pathway

Cholesterol → progesterone → corticosterone → aldosterone

Mineralocorticoids

• hormones involved in balance of salts (Na+, K+) & water in body; essential to life to maintain adequate blood pressure

• primary (95%) mineralocorticoid is aldosterone

Aldosterone

• stimulates reabsorption of Na+ by kidney tubules (K+ out for Na+ in)

• increases Na+ reabsorption from sweat, saliva, gastric juice

• water follows Na+ if water channels are open (ADH!)

Conditions that increase aldosterone release

• increased blood K+

• low blood Na+

• low blood volume/pressure

Mechanisms regulating aldosterone secretion

• renin-angiotensin system

• plasma Na+/K+

• ACTH

• plasma ANF (atrial natriuretic factor)

Renin-angiotensin system

• major regulator of aldosterone secretion

angiotensinogen (from liver) -(renin from kidney)→ angiotensin 1 -(ACE)→ angiotenin 2

Plasma [Na+] or [K+]

low Na+ or high K+ stimulates aldosterone secretion

ACTH

Hypothalamic-Pituitary Axis

CRH (hypothalamus) → ACTH (anterior pituitary) → aldosterone (zona glomerulosa) usually ACTH (not specific to just aldosterone!!) a minor player - comes into effect if individual severely stressed

Atrial Natriuretic Factor (ANF)

• released by heart when blood pressure rises

• effects on aldosterone secretion are inhibitory; goal is to decrease blood pressure by allowing Na+ and water to leave body via urine

Zona Reticularis

• primary product is DHEA (dehydroepiandrosterone)

• much smaller amounts of estrogen produced in both males & females

• amounts of both androgens and estrogens are insignificant compared to gonadal production of these steroids from late puberty on

Function of DHEA in females

• onset of puberty to promote growth of pubic and axillary hair, enhance pubertal growth spurt and promote sex drive

• important source of substrate for estrogen production post menopause (protect against osteoporosis)

Regulation of sex steroid secretion by the adrenals

• not completely understood

• can be stimulated by ACTH, but no negative feedback, so not really controlled by ACTH and levels rise markedly during puberty and this is not driven by ACTH

Hypersecretion of what can lead to masculinizing in females (e.g. hirsutism)

Hirsutism