As down the bone that is formed

As
of 2014, fifty-four million Americans had reported low bone density. Of these
fifty-four million people, approximately ten million of them had been diagnosed
with osteoporosis. Osteoporosis is a disease which simply means ‘porous bone’
and occurs when a person’s bones significantly lose mass and become porous,
leaving them extremely fragile. This bone fragility increases the risk of bone
breakages or fractures in the affected person. There are currently no real
symptoms of osteoporosis; it is because of this, that the affected person is
rarely diagnosed before the first fracture occurs. Though, researchers have
been looking into potential biomarkers to assist doctors in the diagnosis of
osteoporosis before the first fracture even happens.

             The cell
and membrane structure and function of cells involved in osteoporosis. The
two cells which are responsible for bone formation and resorption are
osteoblasts and osteoclasts, eukaryotic cells with multiple nuclei as well as a
prominent mitochondria and Golgi apparatus (Caetano-Lopes et al., 2007). The
membranes of both cells contain proteins such as –ATPase, IGF2R, TRAP, and
cathespin K which are significant in the overall function of the cells (Ha et
al., 2008). Osteoblasts, the cells which lay down new bone mineral do so by secreting
a dense layer of collagen called the organic matrix. This secretion of matrix
involves the deposition of an extremely dense hydroxyapatite-based mineral into
the organic matrix to provide strength. This process of matrix secretion is
driven by active and passive transport as well as pH control (Blair et al.,
2017). Osteoclasts on the contrary, are the cells which break down the bone
that is formed by osteoblasts. This resorption is promoted initially by
endocytosis (ingestion of matter by the cell), followed by transcytosis
(transportation of small molecules from one side of a cell to the other), of
degraded bone matrix. This cycle of bone formation and resorption is called
bone remodeling (Blair, 1998). These two very similar yet strikingly
differently cells and their processes go hand-in-hand and when functioning
properly, bone remodeling results in healthy strong bones.

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            The
metabolic pathways, anabolic and catabolic, present within osteoblasts and
osteoclasts. Mature osteoclasts are able to generate high ATP production
rates due to their high mitochondrial and citric acid cycle respiration. This
ATP is used during bone resorption. Researchers have found that glucose
metabolism is actually increased while osteoclasts are differentiating. During
this increased glucose metabolism, there is a shift towards mitochondrial
respiration. This shift is what allows high ATP production, enhancing
differentiation (Kim et al., 2007). For osteoblasts, studies show that the production
of lactate from glucose without oxygen (aerobic glycolysis) is the main way for
these cells to metabolize glucose. They also show that the lactic acid that is
produced by glucose is stimulated by the calciotropic hormone parathyroid
hormone (PTH). This information has led most researchers to believe that the
increase in lactic acid production is responsible for the increased active bone
resorption (Esen et al., 2014). Osteoblasts contain Teriparatide, an available
form of PTH, which increases bone turnover and the bone density of people
affected by osteoporosis. The parathyroid hormone down regulates the expression
of sclerostin, a protein encoded by the gene SOST, expression in osteocytes
(osteoblast imbedded within the bone matrix) permitting the anabolic signaling
pathway to proceed. The process ultimately improves skeletal microarchitecture by
strengthening it (Silva et at., 2015). At the same time, the PTH receptor
signaling in osteoblasts is responsible for increasing bone the ratio of RANKL/OPG
(OPG is secreted by osteoblasts and prevents too much break down of bone matrix
by osteoclasts through the binding of OPG with RANKL), which then in turn
increases the recruitment of both osteoblasts and osteoclasts as well as
osteoclast activity (resorption) (Boyce & Xing, 2007) (Nissenson, 2002). An
example of these pathways being blocked in nature is the overexpression and/or
inhibition of the Wnt signaling pathways (pathway made of proteins which pass
signals through a cell). When this happens, the cell doesn’t know when to start
or stop secreting bone matrix. If this happens, the tight roles of bone
remodeling would not be balanced, increasing the risk of diseases such as
osteoporosis (Rhee et al., 2013).

            Cellular
respiration and fermentation within osteoblasts and osteoclasts. As stated
in previously, both osteoclasts and osteoblasts both require a great deal of
ATP due to the fact that bone remodeling (bone resorption and formation) is a
process which requires a lot of energy. However, not very much information on the
processes these cells go through to meet this demand for such an extensive
amount of energy is known as of now (Esen & Long, 2014) (Indo et al.,
2013). Though the information on the process these two cells go through to
generate ATP is limited, it is possible to piece together the data that has
been collected by multiple researchers to piece together the possible processes
of cellular respiration of two cells. Researchers have found that throughout
the course of osteoclast differentiation, osteoclasts are capable of increasing
the amount of ATP they produce in order to meet the large demand required for
the bone resorption process. This is thought to be because during osteoclast
differentiation, mitochondrial biogenesis, an increase in the mass of each
cell’s mitochondria, is initiated in an attempt to increase ATP production as a
response to the plethora of energy the cell is expending. Mitochondrial
biogenesis is possible through the uptake of the iron transferrin receptor as
well as the action of beta 1, a peroxisome proliferator-activated
receptor-gamma coactivator. The combination of these two processes take part in
the initial activation of cellular respiration through the provision of iron to
the cells various respiratory proteins (Indo et al., 2013). We can assume the
same goes to osteoblasts due to the fact that the two cells functions go
hand-in-hand and are thought to have similar workings. Osteoblasts perform
aerobic glycolysis with a goal of creating lactate. Though no articles were
able to distinguish which pathway is used in the process, the production of
lactic acid in osteoblasts is possible anaerobically (without oxygen) as well
as aerobically (with oxygen). Depending on the pathway being used, it is
possible that osteoblasts perform lactic acid fermentation as well as aerobic
glycolysis. Either way, the process of lactate formation is thought to play a
key role in the overall function of the cell. This process of aerobic
glycolysis is initiated when the Wnt signaling pathway and parathyroid hormone
(PTH) activate osteoblast differentiation (Esen & Long, 2013). Similar to
the fact that little information is known for sure about the processes
osteoblasts go through to produce large amounts of ATP, little is known about
the source of the high citrate levels in bones. It is thought by researchers
that the high citrate levels may be caused by an altered metabolic reaction in
the Krebs Cycle of cells known to produce greater net citrate (osteoblasts), that
blocks the oxidation of citrate in the cell itself (Costello et al., 2012).
This is just a theory at the moment, though it might be the cause of high
citrate levels within bone tissue. As the osteoblasts mature, they begin
oxidative phosphorylation in order to go through differentiation. The arrival
of glucose and the process of oxidative phosphorylation allows an up-regulation
in the amount of energy teach cell uses. This is necessary for the synthesis of
collagen which is what allows differentiation to actually take place. After
oxidative phosphorylation, the cell is capable of regulating the uptake of this
glucose that is now available, through GLUT transporters (Gentur et al., 2014).

            The
different parts of cell communication within osteoblast and osteoclast cells. Once
gain, based on the idea that osteoblasts and osteoclasts go hand-in-hand and
work off each other and have very similar cellular makeups, it is possible to
gather the information about the receptor proteins involved in one cell and ion
gated channels involved in another, to piece together what the inner workings
of both cells are like. Based on the results of an experiment they conducted, a
group of researchers feel confident that the bone remodeling process and the
presence of GPR103, a G-protein-coupled receptor, in cells involved in the bone
remodeling are directly related. In this experiment, mice that were GRP103
deficient had a lower amount of osteoclasts compared to mice which contained a
respectable amount of GRP103 G-protein-coupled receptors Baribault et al.,
2006). If this proves to be true with time, organisms that are GRP103 deficient
would possibly be less prone to osteoporosis due to the fact that their
osteoblasts would be able to produce bone matrix at a higher rate than osteoclasts
could break it down. Similar to this theory linking osteoclasts and GRP103, a
theory about ligand gated ion channels present in osteoclasts was just
discovered in 2001. It was found that the ligand gated channels present in
osteoclasts consist of glutamate-gated channels as well as P2X nucleotide
receptors. These receptors are thought to act as targets for therapeutic agents
with the purpose of treating bone disorders such as osteoporosis (Komarova et
al., 2001). As or osteoblast cells, it was found that receptor tyrosine kinases
and phosphorylation cascades are both involved in signaling within the cell. During
the transition from pluripotent stem cells to osteoblasts, the expression of
receptor tyrosine kinase Ror2 increases. Receptor tyrosine kinase Ror2 is
responsible for inducing an osteogenic transcription factor, osterix, as well
as well as promote the mineralization of bone matrix. Ror2 is also responsible
for playing a major role in osteoblast differentiation (Liu et al., 2007).
There is a possibility that by promoting mineralization and differentiation,
the amount of mature osteoblasts increases. If this is the case, an increase in
mineralization and differentiation can lead to a decrease in bone disease such
as osteoporosis by creating bone matrix at a faster rate than bone resorption. The
phosphorylation cascade involved in signaling in osteoblasts is when the MAPK
pathway which is stimulated through the induction of MEK(SP), a constantly
active form of MEK1, into MC3T3-E1 pre-osteoblast cells begin to differentiate
and become osteoblasts. When MEK(DN), a dominant negative mutant, is introduced
to the cascade, the process was inhibited and osteoblast differentiation did
not take place (Xiao et al., 2000). This inhibition of the phosphorylation
cascade could be a potential cause of osteoporosis due to the fact that
osteoblasts are unable to differentiate and produce bone matrix. Along with the
involvement of phosphorylation cascades and ligand gated ion channels in the
signaling in osteoblasts, the cells use PTH to stimulate the secretion of
neutral collagenase, an enzyme which plays a part in the the turnover of bone
matrix as well as stimulate the signal transduction which involves
protein-kinase C (PKC), making calcium ions second messengers used for
signaling in osteoblasts (Civitelli et al., 1989).

            The
cell cycle of osteoblast cells. While osteoblasts and osteoclasts are very
similar in that they are both somatic cells with 46 chromosomes per cell, the
way they are formed is quite different. An osteoblast cell is formed from an
osteogenic cell. Osteogenic cells are stem cells which are found within the
tissue on the outer layer of bones, after these cells go through
differentiation, they become osteoblasts. These cells reproduce asexually
through mitosis and similar to most other cells spend a majority of mitosis in
interphase in the G1 phase (Reece et al., 2014). It is during this period of
time that cell cycle misregulation may take place. An example of cell cycle
misregulation in ostegenic cells is the inhibition of proteasomes by MG132
blocks the cell cycle. By blocking the cell cycle, the down regulation of Runx2
in osteoblasts is no longer possible. In a study using mice, researchers
concluded that mice which lack the protein Runx2 lack a mineralized skeleton.
If this is the case in humans as well, the inhibition of proteasomes in
osteogenic cells may cause a weaker and more fragile porous bone tissue
(osteoporosis). It isn’t until the osteogenic cell completes mitosis and
replicates that the cell goes through osteoblast differentiation and becomes an
osteoblast (San Martin I et al., 2009).

            The
molecular basis of inheritance of osteoblast cells. Before the osteogenic cell splits to
produce a second osteogenic cell, its DNA must first be replicated. The DNA
replication process happens in osteoclasts the same way it would in any other
cell. The double helix unzips with the help of helicase, gets RNA primers with
the help of primase, and gets replicated by DNA polymerase, and the two strains
of DNA are joined by ligase. If there are any mutations on the genes encoding
the DNA replication machinery if osteoblasts such as the lack of the gene
Recql4 during differentiation, it is likely that Rothmund Thomson Syndrome will
become present in the person with this mutation. Rothmund Thomson Syndrome is
linked with decreased bone mass in organisms. In a study which involved mice,
it was found that mice which lacked the Recql4 gene had significantly lower
bone mass than mice in which the Recql4 gene was present (Ng et al., 2015). Low
bone mass causes weak porous bone, hence a lack of the Recql4 gene in humans is
likely to cause osteoporosis.

            The
most interesting point of view in relation to Osteoporosis, osteoblasts, and
osteoclasts. The point of view I found to be the most interesting for my
topic was point of view 3. Point of view 3 was about cellular respiration and
fermentation within osteoblasts and osteoclasts. The reason I chose this point
of view as the most interesting is because based on the research I did on my
two cells for this POV, there was very little definite answers to questions
about the processes they go through and how they are able to do the things they
do (Indo et al., 2013) (Esen & Long, 2014) . The fact that researchers
aren’t certain of how the bone matrix that is secreted from osteoblasts has
such high citrate levels, is simply amazing to me (Costello et al., 2012).

            What
else I would like to know, and why researching osteoporosis from the point of
view of the processes involved in cellular respiration is important. If I
were to pursue this work further, I would want to know the answer to a question
Dr. Kelly had brought to my attention while editing this POV, when osteoblasts
perform aerobic and anaerobic glycolysis and produce lactic acid, what pathway
is being used when the cell produced the acid anaerobically? Is this considered
fermentation? When I looked into finding the answer to this question I didn’t come
up with much, so it would be interesting to find the answer (Esen & Long,
2013).  I am also curious to know the
exact process osteoblasts go through to produce bone matrix with such high
levels of citric acid (Costello et al., 2012). I believe it is important for
continued research to be done on osteoporosis from the point of view of
cellular respiration and fermentation because this is the POV I found had the
most unanswered questions and/or theories being looked into rather than known
knowledge and I feel that if more research is done and we know more about the
process osteoblasts and osteoclasts go through in order to do the things they
do, we can use this information to try and find a way to better prevent or even
cure bone diseases such as osteoporosis.

 

Citations       

 

1.        
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2.        
Ha
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Chun SY, et al. Proteomic profile of osteoclast membrane proteins:
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3.        
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Blair HC. How the osteoclast degrades bone.
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5.        
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J-M, Jeong D, Kang HK, Jung SY, Kang SS, Min B-M. Osteoclast Precursors Display
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Stage of RANKL-Stimulated Osteoclast Differentiation. Cellular Physiology and
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Esen
E, Long F. Aerobic Glycolysis in Osteoblasts. Current Osteoporosis Reports.
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BC, Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the
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8.        
Boyce
BF, Xing L. 2007. The RANKL/RANK/OPG pathway. Curr Osteoporos Rep. 5(3):98-104.

9.        
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RA. Osteoblast signaling and bone anabolism. BoneKEy-Osteovision. 2002. 

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