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d.h
Bone Wo en bone
Woven bone
Lamellar bone
1 Immature bone formed 1.
1 Mature bone that is 1.
rapidly as in the fetus or repair of an injury.
2. Collagen is irregularly arranged.
physically stronger.
2. Collagen is regularly arranged
Bone Structure
 Bone Matrix:
 Consists of organic and inorganic components.
 1/3 organic and 2/3 inorganic by weight.
weight
 Organic component consists of several materials that are secreted by the osteoblasts:
 Collagen fibers and other organic materials [Type I collagen]
 These (particularly the collagen) provide the bone with resilience and the i h ili
d h ability to resist stretching and twisting.
Inorganic component of b
bone matrix
i
 Consists mainly of 2 salts: calcium phosphate and
calcium
l i
h
hydroxide. d
id  These 2 salts interact to form a compound called calcium hydroxyapatite
hydroxyapatite..
 Bone also contains smaller amounts of magnesium, fluoride, and sodium.
 These minerals give g
bone its characteristic hardness and the ability to resist compression.
Three‐dimensional array of collagen molecules. The rod‐
shaped molecules lie in a staggered arrangement which acts as a template for bone mineralization. Bone mineral is laid down in the gaps. g
Note collagen fibers in longitudinal & cross section and how they occupy space btwn the black bone cells.
 Mineralisation involves osteoblasts secreting vesicles containing alkaline phosphatase.  This cleaves the phosphate groups and acts as the foci ffor calcium and phosphate deposition. l i d h h t d
iti  The vesicles then rupture and act as a centre for crystals to grow on.  More particularly, bone mineral is formed from globular and plate structures, distributed among the collagen fibrils of bone and forming yet larger g
gy
g
structure.
This bone:
a. Has been demineralized
b. Has had its organic component removed
Hormonal control
Hormones important to bone growth and
homeostasis:
•Growth Hormone (GH) –
•The thyroid hormones (e.g. thyroxine)
thyroxine) –
•Testosterone
T t t
• Estrogens ‐
•Calcitonin –
•Parathyroid hormones
•Insulin
•Glucocorticoids
Growth Hormone (GH)
‐from the anterior pituitary
anterior pituitary, this hormone is necessary for normal growth and development of the skeleton. ‐ IGF‐1 also has stimulatory effects on osteoblast and chondrocyte
activity to promote bone growth.
y p
g
A deficiency (hyposecretion) of GH during childhood produces a dwarf dwarf, An excess (hypersecretion) in child , teen produces a giant. giant. Hypersecretion in adulthood produces acromegaly
acromegaly, , a disorder in which the shape of many bones, especially those in the face becomes exaggerated. Pituitary gland The thyroid hormones (e.g.
(e g
thyroxine))
thyroxine
‐ regulate metabolism of most cells including those in bone. Sex hormones
Testosterone - this and other androgens g
are important for growth in mass and density of bone. Testosterone is present in both males and females in varying amounts females in varying amounts. • testosterone (T) and growth hormone (GH) have an anabolic effect anabolic effect on bone and both decrease with aging.
• increased bone density and strength
and strength, •and stimulation of linear growth and bone maturation.
• Estrogens ‐ these hormones are important for growth in length of bone and for bone maintenance. They too are present in varying amounts in both sexes amounts in both sexes. •Reduce bone resorption, increase bone formation
•pubertal growth spurt of both sexes is driven primarily by estrogen, and that the more rapid epiphyseal maturation of prepubertal
girls (vs boys) may be explained by their higher estradiol levels.
levels
•estradiol helps to maintain bone density is by stopping the activation of an enzyme known as caspase‐3. Also called the executioner caspase, caspase‐3 is the central player in initiating the process of apoptosis, or programmed cell death of osteoblasts, the bone cells that aid in the growth and development of new bone and teeth
 Testosterone is primarily  Estrogens are produced primarily by p
y y
secreted in the developing follicles in the testicles of males and ovaries, the corpus luteum, the ovaries of females, although placenta.
and the p
small amounts are also secreted  Follicle‐stimulating by the adrenal glands
hormone (FSH) stimulates the production of estrogen  In the testes the leydig cells in the granulosa cells of [interstitial cells of Leydig] the ovaries.
produce the testosterone
 Some estrogens are also S
t
l produced in smaller amounts by other tissues such as the
h th liver,
li
adrenal d
l glands, and the breasts.  Fat cells also produce estrogen
•At puberty, the rising levels of sex hormones At b t th i i l l f h
(estrogens in females and androgens in males) cause osteoblasts to produce bone faster than the epiphyseal cartilage can divide. •This causes the characteristic growth spurt as well pp y
plate.
p
as the ultimate closure of the epiphyseal
•Estrogens cause faster closure of the epiphyseal
growth plate than do androgens. h l
h d
d
•Estrogen also acts to stimulate osteoblast activity
Parathyroid hormone ‐ this hormone exerts the primary control in calcium homeostasis. Calcium is necessary in the blood for many functions and when its level falls parathyroid hormone is secreted. This hormone uses several methods to raise calcium levels in the blood:
1) increased Vitamin D production. Vitamin D is a hormone whose p
precursor is produced in the skin in response to sunlight and then p
p
g
processed in the liver and kidney to become active Vitamin D3. Vitamin D3 increases calcium absorption in the gut. Without this vitamin calcium is not absorbed to any great degree vitamin calcium is not absorbed to any great degree. 2) Increased reabsorption of calcium in the kidney. Much calcium is l h i h lost to the urine, so when you need more in the blood this is an d i h bl d hi i important source. 3) Resorption of bone. PTH increases osteoclastic activity to release calcium into the blood.
Parathyroid Hormone


Released by the cells of the parathyroid gland in response to low blood [Ca
[ 2+]].Causes blood [Ca
[ 2+]] to increase.
PTH will bind to osteoblasts and this will cause 2 things to occur:
 The osteoblasts will decrease their activity and they will release a chemical known as osteoclast stimulating factor release a chemical known as osteoclast‐stimulating factor.  Osteoclast‐stimulating factor will increase osteoclast
activity.
 PTH increases calcitriol synthesis which increases Ca2+
absorption in the small intestine.
 PTH decreases urinary Ca
PTH d
i
C 2+ excretion and increases urinary i d i
i
phosphate excretion. Parathyroid gland, chief and oxyphil cells
Normal parathyroid glands as seen during a thyroidectomy. The large arrow points to the superior parathyroid. The thinner arrow points to the inferior parathyroid. The forceps points toward the recurrent laryngeal nerve. The patient's head is toward the right.
Calcitonin = Thyrocalcitonin
•Normally important only in children, •produced in humans primarily by the parafollicular
f
cells (also known as C‐
cells (also known as C‐cells) of the thyroid,
thyroid, clear cells (C cells)
•Its function is to stimulate the uptake of calcium into growing bone and the deposition of bone matrix. • It acts to reduce blood calcium (Ca2+), opposing the effects of
) opposing the effects of parathyroid hormone (PTH)
•Calcitonin stimulates osteoblast to produce bone and store calcium
p
•Secretion of calcitonin is stimulated by:
•an increase in serum [Ca2+]
•gastrin and pentagastrin
Calcitonin
 Released by the C cells of the thyroid gland in response to high blood [Ca2+].
 Calcitonin acts to “tone down” blood calcium levels.
C l it i t t “t d
” bl d l i l l
 Calcitonin causes decreased osteoclast activity which results in decreased break down of bone matrix and decreased calcium being released into the blood.
 Calcitonin also stimulates osteoblast activity which means calcium will be taken from the blood and deposited as bone matrix.
Notice the thyroid follicles on the right The arrow right. The arrow indicates a C cell
The hormone participates in calcium (Ca2+) and phosphorus metabolism.
2 levels in three ways:
More specifically,
f
calcitonin lowers blood Ca
C 2+
•
Inhibits Ca2+ absorption by the intestines
•
Inhibits osteoclast activity in bones
•
Inhibits renal tubular cell reabsorption of Ca2+ allowing it to be
secreted in the urine
•Vitamin D regulation
In its skeleton-preserving actions, calcitonin protects against calcium loss from
skeleton during periods of calcium mobilization, such as pregnancy and,
especially,
p
y, lactation
While calcitonin is the antipode of parathyroid hormone (PTH) in those actions,
it is similar to PTH in its effect on electrolyte reabsorption in the kidneys.
Namely, calcitonin:
•
Inhibits phosphate reabsorption by the kidney tubules
•
Decreases tubular reabsorption of Ca2+, leading to increased rates
of its loss in urine.[11]
Oth effects
Other
ff t are iin preventing
ti postprandial
t
di l hypercalcemia
h
l
i resulting
lti ffrom
absorption of Ca2+...
Other hormones that affect bone growth include g
insulin and the glucocorticoids.
•Insulin stimulates bone formation
•Glucocorticoids inhibit osteoclast activity.
Bone remodeling (or bone metabolism
bone metabolism) ) •Is a lifelong process where mature bone tissue is removed from the skeleton (a process called bone resorption) and new bone tissue i f
is formed (a process called
d ( ll d ossification
ifi ti or new bone formation). b f
ti ) •These processes also control the reshaping or replacement of bone following injuries like fractures but also micro‐damage, which occurs during normal activity. Remodeling responds also to functional demands of the mechanical loading.
functional demands of the mechanical loading
•In the first year of life, almost 100% of the skeleton is replaced. In adults, remodeling proceeds at about 10% per year.
d lt d li d t b t % •An imbalance in the regulation of bone remodeling's two sub‐
processes, bone resorption and bone formation, results in many metabolic bone diseases, such as osteoporosis
Bone homeostasis
 Bones continually being remodelled
 5‐7% of bone mass turned over each week
5 7% of bone mass turned over each week
 Remodelling regulated by two control mechanisms:
 hormonal control of blood Ca2+ homeostasis
 mechanical stress
Hormonal control of remodelling
o o a co t o o e ode g
 Hormonal control of remodelling acts to maintain blood calcium homeostasis rather than integrity of skeleton
 Blood calcium homeostasis
 Parathyroid hormone (PTH) released when blood Ca2+ low low ‐ stimulates osteoclasts
 Also promotes Ca2+ absorption in GI tract and reduces filtration at kidney
 Calcitonin released when blood Ca2+ high
 inhibits osteoclasts
 stimulates osteoblasts
i l
bl
Calcitonin Negative Feedback Loop
Increased Blood [Ca2+]
Increased calcitonin
release from thyroid C y
cells.
Decreased osteoclast
activityy
Increased osteoblast activity
Anna Swan with her parents
CALCIUM METABOLISM •Calcium is the most abundant mineral in the human body.
•The average
g adult body
y contains in total approximately
pp
y 1 kg,
g,
99% in the skeleton in the form of calcium phosphate salts.
•The extracellular fluid (ECF) contains approximately
22.5 mmol, of which about 9 mmol is in the serum.
•Approximately
A
i
l 500 mmoll off calcium
l i
iis exchanged
h
db
between
bone and the ECF over a period of twenty-four hours
•The amount of total calcium varies with the level of serum albumin, a protein to which calcium is bound.
The serum level of calcium is closely regulated with a normal total calcium of 2.2‐
2.6 mmol/L (9‐10.5 mg/dL) and a normal ionized calcium of 1.1‐1.4 mmol/L (4.5‐
5.6 mg/dL). Corrected calcium (mg/dL) = measured total Ca (mg/dL)
+ 0.8 (4.0 - serum albumin [g/dL]),
where 4.0 represents the average albumin level in g/dL.
in other words, each 1 g/dL decrease of albumin will decrease 0.8 mg/dL in measured serum Ca
and
d thus
th 0.8
0 8 mustt be
b added
dd d to
t the
th measured
d Calcium
C l i
to
t gett a corrected
t dC
Calcium
l i
value.
l
Or: Corrected calcium (mmol/L) = measured total Ca
(mmol/L) + 0.02 (40 - serum albumin [g/L]),
where 40 represents the average albumin level in g/L
Calcium
 Important signal molecule
p
g
 Part of intercellular cement that holds cells together at tight junction
 Cofactor in the coagulation cascade
 Affects the excitability of neurons
Calcium Balance in the Body
Small intestine
Dietary
calcium
Calcium
in feces
Ca2+
C l it l
Calcitrol
(PTH, prolactin)
ECF
Bone
Calcitonin
Ca2+
Some calcium is secreted
into the small intestine.
PTH
Kidney
Passive
filtration
[Ca2+]
2.5 mM
Calcitriol
PTH
Ca2+ in
kidney
tubules
Calcitonin
Cortisol
Electrochemical
gradient
Active
transport
Cells
[free Ca2+]
0 001 mM
0.001
M
KEY
Ca2+
in urine
PTH = parathyroid
hormone
Figure 23-20
Calcium Balance
Osteoclasts are responsible for bone resorption Figure 23-21
Calcium Balance
 Parathyroid hormone
 Mobilizes calcium from bone
 Enhances renal reabsorption
 Indirectly increases intestinal absorption
 Vitamin D (Calcitriol)
 Calcitonin (from Thyroid)
Nutritional Effects on Bone
 Normal bone growth/maintenance cannot occur w/o sufficient dietary intake of calcium and phosphate salts.
 Calcium and phosphate are not absorbed in the intestine unless the hormone calcitriol is present. is present  Calcitriol synthesis is dependent on the availability of the steroid cholecalciferol
h l l f l (a.k.a. Vitamin D)
k
which may be synthesized in the skin or obtained from the diet.
 Vitamins C, A, K, and B12 are all necessary for bone growth as well.
Different Forms of Vitamin D
Cholecalciferol
vitamin D3
Cholecalciferol is the naturally occurring form of vitamin D.
Cholecalciferol is made in large quantities in your skin when sunlight strikes your
bare skin. It can also be taken as a supplement.
Calcidiol
25(OH)D or 25D Calcidiol Made in Liver AFTER BEING ABSORBED BY SKIN OR INJESTION
Calcidiol (25-hydroxyvitamin D) is a prehormone in your blood that is directly made
from cholecalciferol. When being tested for vitamin D deficiency, calcidiol is the only
blood test that should be drawn. When someone refers to vitamin D blood levels,
they are referring to calcidiol levels. Your doctor can order calcidiol levels but the lab
will know calcidiol as 25-hydroxyvitamin D.
Calcitriol
1,25(OH)2D3 or 1,25D3
Calcitriol (1,25-dihydroxyvitamin D) is made from calcidiol in both the kidneys and in
other tissues and is the most potent steroid hormone derived from cholecalciferol.
C l it i l has
Calcitriol
h powerful
f l anti-cancer
ti
properties.
ti
It is
i sometimes
ti
referred
f
d to
t as the
th
active form of vitamin D. Calcitriol levels should never be used to determine if you
are deficient in vitamin D.
Calcium Balance
Endocrine Control of Calcium Balance
Figure 23-23
Calcitonin
Ca
c to
Hormonal Control of Blood Ca
Calcitonin
stimulates
calcium salt
deposit
in bone
PTH;
calcitonin
secreted
Thyroid
Th
roid
gland
Rising blood
Ca2+ levels
Calcium homeostasis of blood: 9–11 mg/100 ml
Falling
F
lli blood
bl d
Ca2+ levels
Thyroid
gland
Osteoclasts
degrade bone
matrix and release
Ca2+ into blood
Parathyroid
glands
PTH
Parathyroid
y
glands release
parathyroid
hormone (PTH)
Figure 6.11
Decreased Blood [Ca2+]
Increased PTH release by parathyroid gland
Binds to osteoblast causing decreased osteoblast activity and release of osteoclast‐
stimulating factor
Increased calcitriol synthesis
Decreased Ca2+
excretion
Increased intestinal Ca2+
absorption
OSF causes increased osteoclast activityy
Decreased bone deposition and ec eased bo e depos t o a d
increased bone resorption
Increased Blood [Ca2+]
Potential positive interactions
•Vitamin D is an important co‐factor in the intestinal absorption of calcium, as it increases the number of calcium binding proteins, involved in calcium absorption through the apical membrane
b
off enterocytes in small intestine. ll
•It also promotes re‐absorption of calcium in the kidneys.
Potential negative interactions
"Unesterified long‐chain saturated fatty acids, i.e. palmitic acid, have a melting point above body temperature and, with sufficient calcium in the intestinal lumen, form b b d t
t d ith ffi i t l i i th i t ti l l
f
insoluble calcium soaps."
•Sodium binding to calcium
•Phytic
y acid binding to calciuM
g
•Oxalic acid binding to calcium
•Caffeine binding to calcium[
•Cortisolbinding to calcium
•Low pH food and proteins (the latter promotes gastric acid)
Response to Mechanical Response to Mechanical Stress
Stress
Wolff’s law – a bone grows or remodels in response to the forces or demands placed upon it
Figure 6.12
Osteoporosis
Normal bone (left) and bone loss in osteoporosis (right) Figure 23-24
Decalcified Bone Matrix
This cross section of a long bone shows cortical bone to the right and bone marrow to the left. The white circles in the marrow are fat cells. In this preparation calcium has been removed during tissue processing. Decalcified Bone Matrix
Osteoclasts (blue) are responsible for degradation of old bone. Be careful, do not (
)
p
g
,
mistake the large multinucleate osteoclast with the equally large megakaryocyte. The megakaryocyte (green) has a single multi‐lobed nucleus. Mechanical control of remodelling
 Hormonal control determines when remodelling
will occur
 Mechanical stress determines where remodelling
g
occurs
 Mechanical loading reduces osteoclast
h i l l di
d
l sensitivity to ii i
PTH