Osteoporosis, a disorder characterised by porous and weak bones, is a major hazard to skeletal health. As the foundation of the human body, bones provide critical structural support. When bone mass decreases, it not only weakens this support but also lowers general function, resulting in a lower quality of life.
With an ageing population and a rise in
osteoporosis cases, the burden on healthcare resources for long-term care is
clear. As a result, there is a need to understand the mechanisms that cause
osteoporosis and develop effective targeted therapeutics to mitigate its
long-term effects.
Osteoblasts and osteoclasts are two types of
cells that play critical roles in bone tissue maintenance and remodelling.
Osteoblasts are bone-forming cells that synthesise and deposit new bone tissue,
whereas osteoclasts break down and remove old or damaged bone tissue. Increased
proportion of osteoclasts causes bone mass loss in situations such as
osteoporosis, rheumatoid arthritis (joint inflammation), and bone metastases
(cancer that has spread to the bones). Osteoclasts develop from the development
of macrophages or monocytes, two types of immune cells. Suppressing osteoclast
differentiation could thus be used as a therapeutic technique to prevent bone
loss. However, the precise molecular pathways driving the complicated process
of bone remodelling are unknown.
In a new groundbreaking study, Professor
Tadayoshi Hayata, Mr. Takuto Konno, and Ms. Hitomi Murachi from Tokyo
University of Science, along with their co-workers, delved deeper into the
molecular regulation of osteoclast differentiation. Receptor activator of
nuclear factor kappa B ligand (RANKL) stimulation induces the differentiation
of macrophages into osteoclasts. Further, bone morphogenetic protein (BMP) and transforming
growth factor (TGF)-b signaling pathways have been implicated in the regulation
of RANKL-mediated osteoclast differentiation. In the current study, the
researchers sought to investigate the role of Ctdnep1 - a phosphatase (an
enzyme that removes phosphate groups) that has been reported to suppress BMP
and TGF-b signaling.
Giving further insight into their work set to be
published on July 30, 2024, in Volume 719 of Biochemical and Biophysical
Research Communications, Prof. Hayata states, "RANKL functions as an
'accelerator' for osteoclast cell differentiation. Driving a car requires not
only the accelerator but also the brakes. Here, we find that Ctdnep1 functions
as a 'brake' on osteoclast cell differentiation."
First, the researchers examined the expression
of Ctdnep1 in mouse-derived macrophages treated with RANKL and untreated
control cells. They noted that Ctdnep1 expression remained unchanged in
response to RANKL stimulation. However, it localized in the cytoplasm in
granular form in the macrophages and differentiated into osteoclasts, distinct
from its normal peri-nuclear localization in other cell types, indicating its
cytoplasmic function in osteoclast differentiation.
Further, Ctdnep1 knockdown (downregulation of gene
expression) resulted in an increase in tartrate-resistant acid
phosphatase-positive (TRAP) osteoclasts; wherein TRAP is a marker for
differentiated osteoclasts. Additionally, Ctdnep1 knockdown led to an increase
in the expression of crucial differentiation markers including 'Nfatc1', a
RANKL-induced master transcription factor for osteoclast differentiation. These
results support the 'brake function' of Ctdnep1, whereby, it negatively
regulates osteoclast differentiation.
Moreover, Ctdnep1 knockdown also led to
increased absorption of calcium phosphate, suggestive of the suppressive role
of Ctdnep1 in bone resorption. Lastly, while, Ctdnep1 knockdown did not alter
BMP and TGF-b signaling, cells deficient in Ctdnep1 showed elevated levels of
phosphorylated (activated) proteins downstream of the RANKL signaling pathway.
These findings suggest that the suppressive effect of Ctdnep1 in osteoclast
differentiation may not be mediated by BMP and TGF-b signaling, but, through
the negative regulation of RANKL signaling and Nfatc1 protein levels.
Overall, these findings provide novel insights
into the process of osteoclast differentiation and reveal potential therapeutic
targets which can be pursued to develop treatments that address bone loss due
to excessive osteoclast activity. In addition to diseases characterized by bone
loss, Ctdnep1 has also been reported as a causative factor in medulloblastoma -
a childhood brain tumor. The authors are, therefore, optimistic that their
research can be extended to other human diseases beyond bone metabolism.
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