by Rami Khoury
Osteopetrosis is a rare metabolic bone disease characterized by generalized
increase in skeletal mass. It is inherited in a number of mammalian species,
including man, and result from congenital defect in the development or function
of osteoclast. Several forms of osteopetrosis have been discovered with
overlapping clinical and radiographic features. The disorder is inherited
in two forms. The first is autosomal recessive with manifestations in the
newborn and a progressive course leading to death in early age. The second
is autosomal dominant which is usually milder disorder with delayed manifestations
that could carry with the patient into adult life. In each of the cases,
consequent impairment of bone resorption prevents formation of bone marrow
cavities, causing delayed or absent tooth eruption and results often in
abnormally shaped bone. There are different forms of mutation for each of
the autosomal recessive and dominant disease. The different forms of mutations
are derived from changes in different genes that code for proteins on the
signaling pathway of osteoclast synthesis. In order to understand the osteoclast
pathway one must understand what are osteoclast and how they are synthesized.
Osteoclast are cells in the bone matrix responsible for degrading old bone,
while concurrently osteoblasts lay down new bone to fill in the excavated
tunnel. The osteoclasts originate, like macrophages, from hemopoietic stem
cells in the bone marrow. These precursor cells are released as monocytes
into the bloodstream and collect at sites of bone resorption. There activation
is influenced by factors secreted by the osteblasts, and other factors.
Osteoblastic stromal cells play an important roll in modulating the differentiation
of osteoclast proginators in two different ways: one is the production of
osteoclast inducing factor (OIF), and two is cell-to-cell recognition between
osteoclast progenitors and osteoblastic stromal cells.
A number of OIF as well as systemic hormones induce osteoclast differentiation.
They are classified into three categories in terms of the signal transduction:
Vitamin D receptor-mediated signals [1 alpha,25(OH)2D3]; protein kinase
A-mediated signals (PTH, PTHrP, PGE2, and IL-1); and gp130-mediated signals
(IL-6, IL-11, oncostatin M, and leukemia inhibitory factor). [Ref 4]. All
of these OIF appear to act on osteoblastic cells to induce osteoclast differentiation
factor, which recognizes osteoclast progenitors and prepares them to differentiate
into mature osteoclasts. An example of OIF is the mutation in the Csfm gene
leading to osteopetrosis. A study in homozygous mice for the recessive mutation
show that fibroblasts cells are defective in the production of functional
macrophage colony-stimulating factor (M-CSF). An interesting discovery in
this research was that they found the Csfm mRNA to be present at normal
levels. This suggests that the mutation is within the Csfm gene itself.
After sequencing the Csfm complementary DNA prepared from op/op fibroblast,
a single base pair insertion was found in the coding region of the Csfm
gene that generates a stop codon 21 base pair down stream. Thus the pathological
changes in this mutant results from the absence of M-CSF. [Ref 1].
The second type of mutation is responsible for osteoclast cell-to-cell adhesion
and recognition. To demonstrate this mutation, experimental gene disruption
in mice of the c-src proto-oncogene encoding a non receptor tyrosine kinase
was performed. The results were that osteoclast were present but inactive.
This is due to an impaired ability of osteoclasts to adhere to the bone
surface and form bone-resorbing ruffled borders. Osteopontin (OPN), a secreted
phosphoprotein, mediates osteoclast adherence to the bone matrix. It was
found in the same study that mice with the c-src mutation expressed OPN
mRNA and protein at a significantly reduced levels as compared with normal
mice. This suggest a roll for the proto-oncogene c-src in the regulation
of OPN gene expression. Even more interesting, it was found that OPN gene
expression can be induced by treatment with epidermal growth factor (EGF)
and 12-O-tetradecoanoyl phorbol-13-acetate (TPA). Thus indicating that c-src
and EGF may regulate OPN gene expression through a common signaling pathway.
There are many studies being conducted on how osteopetrosis work. The key
element to understand this disease is to first learn how the osteoclast
are regulated and function. Many different mutation have already been discovered
that produce osteopetrosis. There does not seem to be a constant cause,
although its found that osteopetrosis is detected much more in close sibling
marriages that are related in blood. Its also known that whether the disease
is inherited as recessive or dominant, the phenotype and onset of expression
varies. In the first example where OIF play a roll, the disease can be cured
by transplantation of the hemopoietic cells. In other cases, bone marrow
transplantation has also been successful in curing human osteopetrosis.
This together with the variability in the age of onset and severity of clinical
aspects, suggests that a multiplicity of genetic mutation may cause the
An example of the dominant mutation is presented here by a pedigree of the
As seen in Jack Neumans case, the dominant mutation is not always expressed.
This form of the mutation is referred to as incomplete penetrance. Even
though Jack carries the mutation he does not express it. Since Nikkei doesn't
carry the mutant, then Jack must of past on the mutation, and some how its
penetrant in his descendants.
An example of the recessive mutation is presented by the pedigree of Barbers
family. In which no one in three generations showed any sign of osteopetrosis,
however when two cousins in the third generation were married, two out of
three of their offspring expressed the phenotype of osteopetrosis. Its interesting
to notice that two out of three express the mutation. Normally we would
have expected the classical 3:1 ratio. However, like the dominant form,
osteopetrosis is derived from a multiple forms of mutations.
1. The murine mutation osteopetrosis is the coding region of the macrophage
stimulating factor gene. Nature. Vol. 345, May 1990.
2. Osteopetrosis in Src-deficient mice is due to an autonomous defect of
Biology. Vol. 90, May 1993.
3. Chipping away at marble-bone disease. The New England Journal of Medicine.
332, June 15, 1995.
4 Modulation of osteoclast differentiation by local factors. School of Dentistry,
University, Tokyo, Japan.
5 Recent developments in the understanding of pathophysiology of osteopetrosis.
Department of Pathophsiology, University of Berne, Switzerland.
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