MDC Researchers Unravel Key Mechanism in Pathogenesis of Osteoporosis
In
osteoporosis, excessive bone resorption occurs. The bones lose their density
and are therefore prone to breakage. Even minor falls can lead to serious bone
fractures. The interplay between two cell types determines bone density: bone
forming cells (osteoblasts) and bone resorbing cells (osteoclasts). The
equilibrium between these two cell types is strictly regulated to prevent the
formation of either too much or too little bone.
LAP and LIP maintain the balance
Dr. Smink,
Dr. Bégay, and Professor Leutz have now elucidated a complicated mechanism
which maintains the equilibrium between bone formation and bone resorption.
Here, the gene switch C/EBPbeta plays a major role. It exists in different
forms, differing in length and number of building blocks. LAP is the term
researchers use to denote the full-length isoform of C/EBPbeta, and LIP is the
term for the short isoform.
LAP
activates another gene switch (MafB) which suppresses the formation of bone
resorbing osteoclasts. In contrast, LIP, suppresses this gene switch and thus
enhances the proliferation and activity of the osteoclasts. As a result, the
osteoclasts resorb more bone substance than is built by the osteoblasts. The
researchers suspect that imbalance in the ratio between LAP and LIP plays a
role in osteoporosis.
The
activity of a signaling molecule – mTOR – determines which of the two isoforms
LAP and LIP is formed. The abbreviation mTOR stands for mammalian Target of Rapamycin. The drug rapamycin
inhibits mTOR and thus suppresses the formation of bone resorbing osteoclasts.
Unfortunately, rapamycin has severe side-effects on the immune system. “In the future, it may be possible
to develop new drugs that regulate the activity of mTOR and, thus, remedy the
disturbance in osteoclast function,” Professor Leutz said.
*Transcription factor C/EBPβ isoform ratio regulates
osteoclastogenesis through MafB
Jeske J. Smink1,4, Valérie Bégay1,4, Ton
Schoenmaker2, Esta Sterneck3, Teun J. de Vries2,
and Achim Leutz1
1 Max
Delbrueck Center for Molecular Medicine,
Berlin, Germany.
2
Departments of Periodontology and Oral Cell Biology, Academic Centre of
Dentistry Amsterdam, Universiteit van Amsterdam and Vrije Universiteit, Amsterdam, The
Netherlands.
3 National
Cancer Institute, Center for Cancer Research, Frederick, MD21702, U.S.A.
4 these
authors contributed equally to this work
Barbara
Bachtler
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