Hello, my name is Michaela Kneissel.
And I'm based at the
for BioMedical Research
I'm going to talk today
about some of the pathways
which control bone formation.
I will start off with a brief
introduction to bone homeostasis
before speaking about three pathways
which regulate bone formation.
I choose to highlight those out
of the range of relevant pathways,
as they are the major pathways
targeted to date for the treatment
of bone diseases and injuries.
First and foremost, I will
introduce you to Wnt signaling,
its crucial role in
bone formation, and how
the pathway is currently targeted
for the treatment of bone fragility.
In particular, I will spend some
time explaining the role and
mode of action of the Wnt
which is a key negative
regulator of bone formation.
I will then also introduce briefly
the impact of parathyroid hormone,
or PTH signaling on
bone formation, and how
it is used to treat osteoporosis.
Finally, I will touch on
the importance of bone
or BMP signaling,
and how its modulation can be
used to promote bone healing
or hinder excessive formation.
And I will highlight some
of the cross-talk that exists
between these three
pathways and the regulation
of bone homeostasis.
The skeleton contains three major
cell types-- osteoblasts and the
derived osteocytes and osteoclasts.
Osteoblasts form bone.
Osteoclasts resorb bone.
And osteocytes maintain bone and
contribute to the regulation of
osteoblast and osteoclast activity.
Bone forming osteoblasts arise from
pluripotent mesenchymal stem cells.
Wnts, PTH, and BMPs are
amongst the key factors
that enable mesenchymal
stem cell differentiation
towards the osteoblast lineage.
together with chondrocytes
from a common
precursors undergo proliferation,
followed by differentiation into osteoblasts.
Osteoblast differentiation requires
activation of the key transcription
factor Runx2, also termed Cbfa1.
which then mineralizes end materials.
At the end of the bone
matrix forming activity,
osteoblasts either undergo apoptosis
or become dormant lining cells
on the bone surface or turn into
The latter represent over
90% of all bone cells,
and are interconnected with each
other in cells on the bone surface
by an extensive canalicular
network in which the osteocyte
dendritic processes are contained.
also exists between cells
of the osteoblastic
lineage and osteoclasts
which are of hematopoietic origin.
The activity of the three
major bone cell types
is coordinated through
autocrine, paracrine, endocrine,
and magneto-sensing signals,
to ensure the maintenance
of appropriate bone architecture
and balance of calcium
In addition, the interaction
of bone with bone marrow
is crucial for hematopoiesis.
The actions of osteoblasts,
osteocytes, and osteoclasts
take place within two settings:
bone modelling and remodeling.
In bone modeling,
bone formation and resorption
occur in an uncoupled manner
and on separate surfaces.
Bone modeling is required for
accrual of appropriate bone
morphology and mass during growth.
Bone modeling also occurs at
a low rate throughout life,
and is necessary
in the adult skeleton
for bone repair and adaptation
to changes in mechanical loading.
Bone remodeling, on the other hand,
is based on the coupled activities
of bone resorption and formation
that occur in packages of cells
on the same bone surface, also termed
the basic multicellular unit.
Bone remodeling enables tissue
turnover in the mature skeleton,
while maintaining bone mass, and
also allows in part for adaptation
to the requirements of calcium
and phosphate metabolism.
Bone loss occurs when the
balance between bone resorption
and formation is disrupted in favor
of osteoclastic bone resorption.
This results in osteoporosis,
which is characterized
by micro-architectural deterioration
of bone and increased fragility,
predisposing to fractures.
The most widely used
treatments for osteoporosis
are, to date,
However, they do not only
decrease bone resorption, but also
bone formation, based on the
coupling of these two processes
during bone remodeling.
Hence destructs/stops bone
loss, but do not restore bone mass.
Since many patients have already
lost a substantial amount of bone
at the time of diagnosis,
the medical community
has been on the outlook
for treatments that
could stimulate bone
formation of new bone
to restore bone mass and strength.
The best path towards
this therapeutic goal
may have been found
only relatively recently.