Bone Is A Mineralized Connective Tissue: Biochemistry Department

Bone is a
mineralized
connective
tissue
Biochemistry Department
Cells of Bone Tissue
Bone contains both organic and inorganic material.
The organic matter is mainly protein. The principal

proteins of bone are listed in Table 489; type I
collagen is the major protein, comprising 9095%
of the organic material.
Type V collagen is also present in small amounts,
as are a number of noncollagen proteins, some of
which are relatively specific to bone.
The inorganic or mineral component is mainly crystalline
hydroxyapatiteCa10(PO4)6(OH)2along with sodium,
magnesium, carbonate, and fluoride; approximately 99% of the
bodys calcium is contained in bone. Hydroxyapatite confers on
bone the strength and resilience required by its physiologic roles.
Bone is a dynamic structure that undergoes
continuing cycles of remodeling, consisting of
resorption followed by deposition of new bone tissue.
This remodeling permits bone to adapt to both
physical (eg, increases in weight-bearing) and
hormonal signals.
Chemical Composition of Bone
Inorganic components make up

Organic components of bone
65% of bone by mass, and consist
include cells (osteoblasts,
of hydroxyapatite (calcium
osteocytes, and osteoclasts) and
phosphate + calcium carbonate),
osteoid (ground substance and
a mineral salt that is largely
collagen fibers), which contribute
calcium phosphate, which
to the flexibility and tensile
accounts for the hardness and
strength of bone.
compression resistance of bone
Osteoblasts are bone
The extracellular matrix
building cells.
is about 25% water,
Synthesize and
25% collagen fibers and
secreteorganic
50% crystalized
component needed to
minerals.
build EC matrix.
Osteocytes are mature

bone cells develop when
osteoblasts are trapped
in lacuna.
Chemical Composition of Bone: Organic
Osteoblasts Osteocytes
bone-forming mature bone
cells cells
Osteoid
Osteoclasts unmineralized
large cells that bone matrix
resorb or break composed of
down bone proteoglycans,
matrix glycoproteins,
and collagen
Copyright 2003 Pearson Education, Inc. publishing as Benjamin Cummings

Osteoclasts are Osteogenic cells are

multicellular stem cells found in
structure responsible the inner portion of
for resorption of the the periosteum.
breakdown of the Osteogenic cells are
EC matrix termed the only ones
resorption. Found in undergoing cell
the periosteum. division.
Chemical Composition of Bone: Inorganic
Hydroxyapatites, or mineral salts
Sixty-five percent of bone by mass

Mainly calcium phosphates
Responsible for bone hardness and
its resistance to compression
Copyright 2003 Pearson Education, Inc. publishing as Benjamin Cummings
Osteoclasts
Resorbe bone matrix from sites where it is

deteriorating or not needed
Digest bone matrix components
Focal decalcification and extracellular
digestion by acid hydrolases and uptake of
digested material
Disappear after resorption
Assist with mineral homeostasis
Chemistry of the bone
Matrix
Mineral
Matrix - osteoid
Collagen type I and IV

Layers of various orientations (add to the
strength of the matrix)
Other proteins 10% of the bone protein
Direct formation of fibers
Enhance mineralization
Provide signals for remodeling
Mineral
A calcium phosphate/carbonate compound

resembling the mineral hydroxyapatite
Ca10(PO4)6(OH)2
Hydroxyapatite crystals
Imperfect
Contain Mg, Na, K
Mineralization of the bone
Calcification occurs by extracellular deposition

of hydroxyapatite crystals
Trapping of calcium and phosphate ions in
concentrations that would initiate deposition of
calcium phosphate in the solid phase, followed by
its conversion to crystalline hydroxyapatite
Mechanisms exist to both initiate and inhibit
calcification
Bone remodeling process
Proceeds in cycles
first resorption than
bone formation
The calcium content of
bone turns over with a
half-life of 1-5 years
Bone remodeling process
Bone remodeling cycle (1)
Endosteal sinus
Monocyte
Pre-osteoclast
Pre-osteoblast
Osteoclast
Osteoblast Bone-lining cell

Osteocyte Macrophage
Osteoid
New bone
Old bone
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Endosteal sinus
Monocyte
Pre-osteoclast
Pre-osteoblast
Osteoclast
Macrophage Osteoblast Bone-lining cell

Osteocyte
Osteoid
New
bone
Old
bone

Pre-osteoblasts
Monocytes
Osteoblasts
Osteoclasts
Osteocytes

Bone Deposition and Resorption
Ca2+ and phosphate concentrations are affected by:

Bone formation and resorption.
Intestinal absorption of Ca2+ and P043-.
Urinary excretion.
Osteoblasts:
Secrete an organic matrix of collagen proteins.
Deposit hydroxyapatite crystals.
Osteoclasts:
Secrete enzymes to dissolve hydroxyapatite.
Formation and resorption of bone occur constantly at rates
determined by osteoblasts and osteoclasts.
Bone Deposition and Resorption (continued)
Bone resorption occurs when an osteoclast attaches to the

bone matrix and forms ruffled membrane.
Osteoclast secretes products that dissolve both Ca2+ and P043-
; and digest the matrix.
Transport of H+ by H+ ATPase pump in ruffled border.
Cl- channel allows Cl- to flow to H+ to maintain electrical neutrality.
Protein matrix digested by cathepsin K.
Cytoplasm prevented from becoming to basic by a Cl-/HC03- pump.

Bone Deposition and Resorption (continued)

Bone Resorption

Figure 4812. Schematic illustration of some aspects of the
role of the osteoclast in bone resorption. Lysosomal enzymes
and hydrogen ions are released into the confined
microenvironment created by the attachment between bone
matrix and the peripheral clear zone of the osteoclast. The
acidification of this confined space facilitates the dissolution of
calcium phosphate from bone and is the optimal pH for the
activity of lysosomal hydrolases. Bone matrix is thus removed,
and the products of bone resorption are taken up into the
cytoplasm of the osteoclast, probably digested further, and
transferred into capillaries. The chemical equation shown in the
figure refers to the action of carbonic anhydrase II, described in
the text. (Reproduced, with permission, from Junqueira LC,
Carneiro J: Basic Histology: Text & Atlas, 10th ed. McGraw-Hill,
2003.)
Coordination of Resorption and
Formation
Phase I
Signal from osteoblasts
Stimulation of osteoblastic precursor cells to
become osteoclasts
Process takes 10 days
Coordination of Resorption and
Formation
Phase II
Osteoclast resorb bone creating cavity
Macrophages clean up
Phase III
New bone laid down by osteoblasts
Takes 3 months
Pathways of differentiation of
osteoclasts and osteoblasts
Hormonal Influence
Vitamin D
Parathyroid Hormone
Calcitonin
Estrogen
Androgen
Vitamin D
Osteoblast have receptors for (1,25-(OH)2-D)

Increases activity of both osteoblasts and
osteoclasts
Increases osteocytic osteolysis (remodeling)
Increases mineralization through increased intestinal
calcium absorption
Feedback action of (1,25-(OH)2-D) represses gene
for PTH synthesis
Parathyroid Hormone
Accelerates removal of calcium from bone to increase Ca
levels in blood
PTH receptors present on both osteoblasts and osteoclasts
Osteoblasts respond to PTH by
Change of shape and cytoskeletal arrangement
Inhibition of collagen synthesis
Stimulation of IL-6, macrophage colony-stimulating factor secretion
Chronic stimulation of the PTH causes hypercalcemia and
leads to resorptive effects of PTH on bone
Parathyroid Hormone (PTH)
Single most important hormone in the control of
blood [Ca2+].
Stimulated by decreased blood [Ca2+].
Stimulates osteoclasts to reabsorb bone.
Stimulates kidneys to reabsorb Ca2+ from glomerular
filtrate, and inhibit reabsorption of P043-.
Promotes formation of 1,25 vitamin D3.
Many cancers secrete PTH-related protein that
interacts with PTH receptors.
Produce hypercalcemia.
Calcitonin
C cells of thyroid gland secrete calcitonin

Straight chain peptide - 32 aa
Synthesized from a large preprohormone
Rise in plasma calcium is major stimulus of
calcitonin secretion
Plasma concentration is 10-20 pg/ml and half
life is 5 min
Actions of Calcitonin
Osteoclasts are target cells for calcitonin

Major effect of calcitonin is rapid fall of plasma
calcium concentration caused by inhibition of
bone resorption
Magnitude of decrease is proportional to the
baseline rate of bone turnover
Calcitonin
Works with PTH and 1,25 vitamin D3 to

regulate blood [Ca2+].
Stimulated by increased plasma [Ca2+].
Inhibits the activity of osteoclasts.
Stimulates urinary excretion of Ca2+ and P043-
by inhibiting reabsorption.
Physiological significance in adults is
questionable.
1,25 Vitamin D3
Pre-vitamin D3 is synthesized in the skin when

exposed to mid-ultraviolet waves.
Pre-vitamin D3 isomerized to vitamin D3 (cholecalciferol).
Cholecalciferol is hydroxylated in liver to form 25
hydroxycholecalciferol.
In proximal convoluted tubule is hydroxylated to
1,25 dihydroxycholecalciferol (active vitamin D3).
Stimulated by PTH.

Production of
1,25 dihydroxyvitamin D3
Insert fig. 19.20

1,25 dihydroxyvitamin D3
(continued)
Directly stimulates intestinal absorption of Ca2+ and

P043-.
When Ca2+ intake is inadequate, directly stimulates
bone reabsorption.
Stimulates reabsorption of Ca2+ and P043- by the
kidney.
Simultaneously raising Ca2+ and P043- results in increased
tendency of these 2 ions to precipitate as hydroxyapatite
crystals.
Stimulated by PTH.
Negative Feedback Control
Insert fig. 19.23

Other systemic hormones
Estrogens
Increase bone remodeling
Androgens
Increase bone formation

Other systemic hormones
Growth hormone
Increases bone remodeling
Glucocorticoids
Inhibit bone formation
Thyroid hormones
Increase bone resorption
Increase bone formation

Hormonal Mechanism
Figure 6.12
Hormonal Control of Blood Ca
Rising blood
Ca2+ levels
Calcium homeostasis of blood: 911 mg/100 ml
Figure 6.11
Thyroid
gland
Rising blood
Ca2+ levels
Figure 6.11
PTH;
calcitonin
secreted
Thyroid
gland
Rising blood
Ca2+ levels
Figure 6.11
PTH;
calcitonin Calcitonin
secreted stimulates
calcium salt
deposit
in bone
Thyroid
gland
Rising blood
Ca2+ levels
Figure 6.11
PTH;
calcitonin Calcitonin
secreted stimulates
calcium salt
deposit
in bone
Thyroid
gland
Rising blood
Ca2+ levels
Figure 6.11
Falling blood
Ca2+ levels
Figure 6.11

Falling blood
Ca2+ levels
Thyroid
gland
Parathyroid
glands Parathyroid
glands release
parathyroid
hormone (PTH)
Figure 6.11

Falling blood
Ca2+ levels
Thyroid
gland
Parathyroid
glands Parathyroid
glands release
parathyroid
hormone (PTH)
PTH
Figure 6.11

Falling blood
Ca2+ levels
Thyroid
gland
Osteoclasts
degrade bone Parathyroid
matrix and release glands Parathyroid
Ca2+ into blood glands release
parathyroid
hormone (PTH)
PTH
Figure 6.11

Falling blood
Ca2+ levels
Thyroid
gland
Osteoclasts
parathyroid
hormone (PTH)
PTH
Figure 6.11
PTH; Calcitonin
calcitonin
stimulates
secreted
calcium salt
deposit
in bone
Thyroid
gland
Rising blood
Ca2+ levels

Falling blood
Ca2+ levels
Thyroid
gland
Osteoclasts
parathyroid
hormone (PTH)
PTH
Figure 6.11
Bone Growth and Calcium Metabolism
Epiphyseal plate new bone growth site

Chondrocytes, osteoblasts & calcification build bone
Copyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings

Calcium Homeostasis
Bone is major storage site for calcium
The level of calcium in the blood depends upon
movement of calcium into or out of bone.
Calcium enters bone when osteoblasts create new
bone; calcium leaves bone when osteoclasts break
down bone
Two hormones control blood calcium levels-
parathyroid hormone and calcitonin.
6-56
Calcium Homeostasis
6-57
Bone Growth and Calcium Metabolism
Figure 23-19: Bone growth at the epiphyseal plate

Calcium Metabolism:
Maintain [plasma]: from diet, from bone "storage",

recycled
Key roles: muscle contraction, bone support, cell
signaling
PLAY Animation: Fluids & Electrolytes: Electrolyte Homeostasis

Calcium Metabolism:
Figure 23-20: Calcium balance in the body

Control of Calcium Balance & Metabolism
Parathyroid H
Calcitrol
Vitamin D
Sun/diet
Calcitonin
Thyroid
C-cells
(Phosphate balance)
Copyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings Figure 23-23: Endocrine control of calcium balance
Osteoporosis:
Disease of Bone Growth & Calcium Metabolism
Bone reabsorption
exceeds deposition
Osteoclasts mobilize
Ca++ to plasma
Factors: inadequate
Ca++ intake, genes,
hormones, smoking
Figure 23-21: Osteoclasts are responsible for bone resorption

PTH, Calcium
& Phosphate
What is cartilage?
Skeletal tissue--maintains certain shape and form

Very resilient (bouncy or rubbery), mostly water
Grows fast--forms embryonic skeleton

Kinds of cartilage
Hyaline cartilage--most common, found in joints

Elastic cartilage--epiglottis, ear
Fibrocartilage--annular fibrosis of intervertebral disk,
menisci of knee

cartilage

Bone Is A Mineralized Connective Tissue: Biochemistry Department

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Bone Is A Mineralized Connective Tissue: Biochemistry Department

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Bone is a

The organic matter is mainly protein. The principal

Inorganic components make up

Osteocytes are mature

Copyright 2003 Pearson Education, Inc. publishing as Benjamin Cummings

Osteoclasts are Osteogenic cells are

Hydroxyapatites, or mineral salts

Sixty-five percent of bone by mass

Resorbe bone matrix from sites where it is

Collagen type I and IV

A calcium phosphate/carbonate compound

Calcification occurs by extracellular deposition

Osteoblast Bone-lining cell

Non Commercial Use Only

Macrophage Osteoblast Bone-lining cell

Non Commercial Use Only

Non Commercial Use Only

Ca2+ and phosphate concentrations are affected by:

Bone resorption occurs when an osteoclast attaches to the

Non Commercial Use Only

Non Commercial Use Only

Non Commercial Use Only

Osteoblast have receptors for (1,25-(OH)2-D)

C cells of thyroid gland secrete calcitonin

Osteoclasts are target cells for calcitonin

Works with PTH and 1,25 vitamin D3 to

Pre-vitamin D3 is synthesized in the skin when

Non Commercial Use Only

Insert fig. 19.20

Non Commercial Use Only

Directly stimulates intestinal absorption of Ca2+ and

Insert fig. 19.23

Non Commercial Use Only

Non Commercial Use Only

Non Commercial Use Only

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Hormonal Control of Blood Ca

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Calcium homeostasis of blood: 911 mg/100 ml

Epiphyseal plate new bone growth site

Copyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings

Figure 23-19: Bone growth at the epiphyseal plate

Maintain [plasma]: from diet, from bone "storage",

PLAY Animation: Fluids & Electrolytes: Electrolyte Homeostasis

Figure 23-20: Calcium balance in the body

Figure 23-21: Osteoclasts are responsible for bone resorption

Skeletal tissue--maintains certain shape and form

Copyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings

Hyaline cartilage--most common, found in joints

Copyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings

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