SKELETAL METABOLISM

1) it occurs in areas of active bone

formation and

o The metabolic function of bone is to

provide a homeostasic mineral
reservoir, for Ca, and other minerals,
especially Mg and P.

2) matures through several

intermediate stages to
hydroxyapatite.
The end result is

o These bone minerals can be

mobilized to maintain systemic
mineral homeostasis.

1) a highly organized amalgam of

protein, primarily collagen,

o This metabolic function of bone

prevails over its structural function in
that calcium and other minerals are
removed from and replaced in bone
to serve systemic homeostatic needs
irrespective of loss of skeletal
structural integrity.

2) mineral, primarily hydroxyapatite

3) hydroxyapatite, has sufficient
structural integrity
4) (serve the mechanical functions of
the skeleton).
5) Upon completion of this process, the
osteoblast becomes encased in bone
and become an osteocyte.

o Bone is also a depository for certain

cytokines and growth factors. (eg
TFG beta)

Mineralization can occur:

o cytokines and growth factors are

released upon its resorption and
exert their effects locally and
systemically.

1) if there is a functionally adequate

local concentration of these ions,
2) if nucleators are present to promote
crystallization, and

Bone consists of a mineral phase and

an organic phase. The major
components are:

3) if local inhibitors of mineralization

are removed.

1) Mineral phase: hydroxyapatite

crystal and

4) While VD is key to providing

sufficient ambient concentrations of
calcium and other minerals to
promote mineralization of osteoid,
this hormone does not seem to exert
a direct regulatory effect on
mineralization.

2) Organic phase: (products of the

osteoblast) type 1 collagen which,
with other bone proteins, comprises
the osteoid matrix of bone.
Bone mineral is present in two
forms in the skeleton:

A given skeletal site in the adult is

remodeled approximately every 3
years.

A. Hydroxyapatite crystals,
Ca10(PO4)6(OH)2, are

Bone mass is acquired up to the

fourth to fifth decade, with a rapid
phase during adolescent growth.

1) the major forms

2) occur in mature bone.

Most of peak bone mass is

genetically determined.

B. Amorphous calcium phosphate;

1

 Women
have approximately 30% less peak
bone mass than men and
experience an accelerated loss after
the menopause.
Both genders experience age-related
loss of bone mass.

bone

surface area

Cortical

80%

trabecular

20%

activity

1/5 of trab.

3% - 10%

more

the CNS has a role in fat and skeletal

metabolism.

annual
turnover

20%-30%

2) osteocytes,
3) osteoclasts, and

1) The adipocyte-derived hormone

leptin inhibits bone mass accrual
through a brain pathway, which
seems two-step:

4) lining cells.
5) Monocytes, macrophages, and mast
cells (mediate certain aspects of
skeletal metabolism).

2) decreasing the release of serotonin

by brainstem neurons that in turn
regulate appetite and bone mass
accrual.

6) Marrow cells.
o The osteoblast forms bone.

3) Serotonin produced by GI cells may

also participate in this pathway.

Osteoblasts express receptors to

many bone-active agents such as

o Bone cells:

o PTH,

Osteoblast

o PTHrP,

Osteoclast

o VD metabolites,

Osteocyte

o gonadal and adrenal steroids, and

Other - marrow elements

o certain cytokines and growth factors.

o The major product of osteoblasts is
type 1 collagen, which along with
other proteins, forms the organic
osteoid matrix that is mineralized to
hydroxyapatite.

o Bone structure:

Cortical bone

Trabecular bone

Mix

Bone Cells:
o Skeletal metabolism is regulated by
bone cells and their progenitors.
o Among the bone cells are
1) osteoblasts,
3

Osteocytes are osteoblasts that

become encased in bone during its
formation and mineralization.

The osteoclast resorbs bone by

attachment (receptors) with
adhesion molecules and by

While their synthetic activity

decreases, the cells develop
processes that communicate as
canaliculi with other osteocytes,
osteoblasts, and the vasculature.

secretion of hydrogen and chloride

ions that dissolve mineral and lytic
proteases, notably
lysosomal proteases active at low
pH and

Osteocytes thus present acres that

permits translocation of bone
mineral during metabolic activity and
can provide exchanges of minerals
from bone matrix.

metalloproteinases and
cysteine proteinases
that dissolve matrix.

o The osteoclast resorbs bone.

o It is a terminally-differentiated, large,
multinucleated giant cell that arises
from hematopoietic marrow
precursors under the influences of

After completing its function, the

terminally-differentiated osteoclast
undergoes apoptosis.

Bone-lining cells may be osteoblast

precursors or function to clean up
resorption and formation debris.
Mast cells can be seen at sites of
bone resorption and may also
participate in this process.
Cells of the immune system play a
key role in bone metabolism,
especially resorption, by their
interactions with bone other cells

o hormones,

o growth factors, and

o cytokines .

o The process of bone formation is

thus balanced by the process of
bone resorption.

Bone Growth, Modeling

and Remodeling:

Bone resorption is mediated by the

osteoclast, a large, multinucleated
cell that is molecularly equipped to
dissolve both the mineral and
organic phases of bone.

o Growth, modeling, and remodeling

are important processes that allow
the skeleton to play its many
important roles.

o The processes of osteoblastmediated bone formation and

osteoclast-mediated bone resorption
can be assessed by measurement in
urine and blood of bone markers.

o Bone grows and models under the

influence of metabolic, mechanical,
and gravitational forces during
growth through adolescence,
changing its size and shape in the
process.

o The markers of bone formation

include

o Bone growth continues until the third

decade.

1) osteoblast products e.g., ALP and

osteocalcin and

o Bone mass continues to increase

until the fourth decade

2) by-products of collagen synthesis

and

Bone in adults renews itself by

remodeling,(old bone is resorbed and
new bone is then formed to replace
it).

3) osteoclasts products (e.g. tartrate

resistant acid phophatase0 and
4) by-products of collagen break down.

Both cortical bone and trabecular

bone remodel, (trabecular is more
metabolically active).

20% of adult bone surface is

undergoing remodeling at any time.
The homeostatic end-point of
skeletal metabolism is to provide the
appropriate amount of ambient
calcium for

Stages of Remodeling:
1) resorption by osteoclasts and
2) formation by osteoblasts.

1) biological functions,

o Remodeling serves

2) structural integrity of the skeleton.

1) repair skeletal (microdamage)

o These metabolic activities of bone

cells can release into blood and urine
certain bone cells and matrix
products that can serve as clinically
useful markers of skeletal
metabolism

2) improve strength in response to

mechanical forces.
o Osteoclasts and osteoblasts
communicate with each other during
remodeling (coupling) and mediated
by local regulatory signals.

o Coupling assures a balance of bone

formation and bone resorption.

RANKL, RANK, and OPG:

5

o The recent elucidation of this novel

pathway of molecular regulation has
provided both a physiologic link
among bone cell functions as well as
a pathogenetic link among cancer
cells, the immune system, and bone
cells in the regulation of the
osteoclastic bone resorption that is
the final cellular mediator of most
cases of hypercalcemia.

1) increased amounts of RANKL, which

can stimulate osteoclasts.
2) interferon gamma (INF), which
opposes the effect of RANKL on
osteoclast mediated bone resorption.
o These molecular participants in the
interaction between bone cells,
tumor cells, and the immune system
are also regulated by several
hormones, growth factors, and
cytokines that mediate increased
bone resorption, both physiologic
and pathophysiologic.

o The molecular participants in this

pathway are the membraneassociated protein named RANKL
(receptor activator of nuclear factor
kappa B ligand,) a member of the
tumor necrosis factor family of
cytokines; its cognate receptor,
RANK, and OPG (osteoprotegerin), a
soluble "decoy" receptor for RANKL.

o They include
o PTH,
o PTHrP,
o TNF,

RANKL is expressed on the surface of

osteoblastic stromal cells.

o PGE2,

By binding to RANK, its receptor, on

osteoclast precursors, RANKL
enhances their recruitment into
the osteoclastogenesis pathway.

RANKL also activates mature

osteoclasts to resorb bone.

RANKL is considered as the longsought "coupling factor" through

which

o vitamin D metabolites,
o IL-1, and TGF

HORMONAL REGULATION
OF SKELETAL AND
MINERAL METABOLISM
PTH:

PTH hormone is an 84-amino-acid

peptide secreted by two pairs of
parathyroid glands

The mature PTH is packaged into

dense secretory granules for
regulated secretion.

1) osteoblasts regulate osteoclasts and

2) bone formation is coupled to bone
resorption.
In the pathophysiology of
hypercalcemia, many of the tumor
cell types that are associated with
cancer-stimulated bone resorption
express a soluble form of RANKL,
sRANKL.

Secretory Regulation of
PTH and the Ca Sensor:
o The major regulatory signal for PTH
secretion is s. Ca.

during the inflammation that can be

associated with malignancy,
activated T-lymphocytes also express

o S. Ca. inversely affects PTH

secretion.
6

o An increase in I. Ca. inhibits PTH

secretion by increasing IC. Ca.
through the release of Ca. from IC.
stores and the influx of EC Ca.
through cell membranes and
channels.
o This mechanism differs from most
cells, where secretion of their
product is stimulated by increased
Ca.
hypermagnesemia can inhibit PTH
secretion and hypomagnesemia
can stimulate PTH secretion.
prolonged depletion of mg will inhibit
PTH biosynthesis and secretion.
Hypomagnesemia also attenuates
the biological effect of PTH by
interfering with its signal
transduction.
Ser. Ca inversely regulates
transcription of the PTH gene, and
increased levels of 1,25dihydroxyvitamin D (1,25-D) inhibit
PTH gene transcription.

PTH

biosynt
hesis

secr
etio
n

Transcri
ption of
the gene

signal
transdu
ction.

hypermagnes
emia

inhi
bit

hypomagnes
emia

stim
ulat
e

Interfer
e

prolonged
depletion of
mg

inhibit

inhi
bit

Ser. Ca

inversel
y
regulate
s

1,25-D

inhibit

other fragments may have their own

biologic actions.

Metabolism and
Clearance of PTH :

Biologic Effects of PTH:

o PTH has a circulating half-life of less

than 5 minutes.
o The hormone is metabolized to
amino-terminal and carboxylterminal fragments in

PTH regulates serum Ca and P

concentrations through its receptormediated, combined actions on
bone, intestine, and kidney.

High levels (primary and secondary

hyperparathyroidism), increase
osteoclastic bone resorption.

Low levels, seem to increase

osteoblastic bone formation, an
effect that has been applicable to
osteoporosis treatment by daily
injections of PTH.

The skeletal effects of PTH are

mediated through the osteoblast,
since they are the major expressor of
the PTH receptor. However,
osteoblasts communicate with
osteoclasts to mediate PTH effects.

o the liver,
o the kidney,
o the PTG and
o blood.
o The carboxyl-terminal fragments are
cleared by GF, so they accumulate in
renal failure.
o All of the classic biological effects of
PTH are mediated by the amino
terminus, PTH1-34, and likely a
subpeptide of this sequence, but
8

This communication seems mediated

through the RANK-OPG pathway.

bone

Int
est
ine

kidney

increase
osteoclastic
resorption

1) increases the Ca reabsorption

(DCT)

increase
osteoblastic
formation

2) inhibits the reabsorption of P

(PT)

flux; for PTHrP, a nuclear localizing

sequence (NLS) has been identified.

Any direct GI effect of PTH on

intestinal Ca or P absorption is weak.

PTH through its stimulating effects

on the renal production of 1,25-D,
promotes the absorption of both.

In the kidney, PTH

Parathyroid Hormonerelated Protein (PTHrP):

1) increases the reabsorption of Ca, (in

the DCT), and
2) inhibits the reabsorption of P
( proximal T), causing hypercalcemia
and hypophosphatemia.

In addition to this shared receptor,

there is accumulating evidence for
the existence of receptors that are
respectively specific for PTH and
PTHrP and for some of their
subpeptides. In fact, a send PTH
receptor, specific for this peptide,
has been cloned.
For PTH, a carboxy-terminal peptide
seems to mediate cellular calcium

10

The major humoral mediator of the

hypercalcemia of malignancy.

A product of many normal and

malignant tissues.

Secreted by many types of

malignant tumors,(breast and lung) ,

Produces hypercalcemia by
activating the PTH/PTHrP receptor.

Produced in many fetal tissues, but

as development proceeds its
expression becomes restricted.

PTHrP expression reappears in adult

tissues when injury or malignancy
occurs.