Bone is a highly dynamic tissue. Every year approximately
10% of an individual’s skeleton is resorbed and new bone is formed, which means
that every 10 years your bones are made of entirely new material. We call this
process “bone remodeling”. As we age, the balance between bone resorption and
bone formation changes, leading to relatively more bone being removed and less
bone being formed – this is called osteopenia, which refers to low bone mass, and
is a normal consequence of aging. When the balance tilts excessively toward the
loss of bone, we refer to it as osteoporosis.
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| Shuler F. ORTHOPEDICS. 2012 |
Osteoporosis is a disease characterized by bone fragility
and an increased incidence of broken bones, which results when an individual’s
bones become thinner and more brittle. Osteoporosis
has long been thought to mainly affect elderly women; however, with the
increasing use of prescription medicines such as glucocorticoids, and the large
number of people leading unhealthy lifestyles, the incidence of osteoporosis is
predicted to significantly increase in the future. In 2002, approximately 43
million people had either osteoporosis or osteopenia, and in 2020 this number
is predicted to grow to nearly 61 million people.
Alterations in bone remodeling – the coupled action of bone
resorption and bone formation – that lead to osteoporosis are a result of
changes in the activities of the cells that carry out these processes. Bones
are made up of three main types of cells: osteoblasts, osteoclasts, and osteocytes.
Osteoblasts are responsible for forming new bone, while osteoclasts eat away (resorb)
the old or damaged bone. Osteocytes are osteoblasts that become entombed within
the newly formed bone matrix, and they are the most abundant cell type
accounting for nearly 90% of the cells. Osteocytes are the main regulators of
the osteoblasts and osteoclasts. Osteocytes are among the main producers of the
cytokine receptor activator of nuclear factor kappa-B ligand (RANKL) and the decoy cytokine receptor osteoprotegerin
(OPG). The ratio of RANKL:OPG controls osteoclast formation because OPG is able
to bind to RANKL and prevent its binding to the RANK receptor. On the
osteoclast precursor surface, the cytokine RANKL binds to the RANK receptor and
activates osteoclast differentiation and function of the osteoclasts, leading
to increased bone resorption. The osteocytes embedded in the bone connect to
each other through outgrowths called cannaliculi, creating networks within the
bone that allow for the bone to sense mechanical stimuli and transmit signals
between the cells.
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| www.medscape.com |
Connexin (Cx) 43, a key protein involved in the formation of
gap junctions, which are intercellular channels between the cells that allow
for cell-to-cell communication. As an individual ages, the levels of Cx43
decrease and the number of dead osteocytes increases. Animal models with an osteocyte-specific
deletion of Cx43 display increased osteocyte cell death, empty lacunae (the
spaces in the bone cortex normally occupied by living osteocytes), and an
increased number of osteoclasts along the bone surface. Experiments studying
MLO-Y4 osteocytic cells lacking Cx43 also found an increase in cell death.
Transfection of the Cx43 back into these osteocytic cells was sufficient to
prevent this increase in cell death observed in this cell line. Osteocytes
lacking Cx43 undergo a specific form of programmed cell death called apoptosis.
The process of apoptosis is initiated through the action of multiple caspase
proteins, including caspase-3. This increase in osteocyte apoptosis leads to
the release of specific molecules and signals, which are involved in
communicating with the osteoblasts and osteoclasts.
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| www.medicographia.com. 2012 |
To study the effects that osteocyte apoptosis has on
osteoclast recruitment, we collected the conditioning media (the media
containing growth factors that is added to cells) from Cx43-silenced and
control MLO-Y4 cells that were either untreated or treated with DEVD, a caspase-3
inhibitor. This conditioning media was then used to treat non-adherent bone
marrow cells that were treated with m-CSF (macrophage colony stimulating
factor) and RANKL to induce osteoclast differentiation. This study found that
blocking osteocyte apoptosis reduced the levels of soluble RANKL and prevented
the increase in osteoclast recruitment and activity associated with osteocyte
cell death.
The overall findings from this study suggest that Cx43 is
required to maintain osteocyte viability and show that the increased osteoclast
activity observed in Cx43 silenced osteocytes is a result of the increased
osteocyte apoptosis. These findings provide a potential way in which osteocyte
apoptosis could be targeted to prevent bone fragility in individuals with low
bone mass.
Currently, the majority of osteoporosis drugs on the market
work to maintain bone mass through inhibiting the activity of the bone
resorbing osteoclasts. While these drugs are effective at preventing further
bone loss, they do not reverse the bone loss that has already occurred before
treatment has begun. This is because bone formation and resorption are coupled
in bone remodeling*, so inhibition of resorption also decreases the amount of
formation. The findings from this study provide evidence that specifically targeting
osteocytes could allow for a therapeutic method to prevent bone loss and
maintain bone mass through mechanisms that do not involve completely inhibiting
the activity of osteoclasts.
* The uncoupled action of bone formation and bone resorption
is referred to as “bone modeling”, which is one of the ways that bones can
change their shape as we grow during childhood and adolescence.
Contributed by:
Hannah Davis
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