Malignant Infantile Osteopetrosis
Tyler Patterson, Taylor Quiros, and Ashwin Adivi
Department of Biology, Trinity University
OSTEOPETROSIS INTRODUCTION
MECHANISMS OF OSTEOPETROSIS
Osteopetrosis is a rare genetic disorder that results
in decreased bone reabsorption by osteoclasts,
leading to an abnormally high skeletal bone density.
The disease leads to brittle bones and decreased
amounts of bone marrow, which causes secondary
complications involving blood components. There
are thought to be three genetic causes of
osteopetrosis—autosomal dominant, autosomal
recessive, and X-linked inheritances. This project
will focus on the malignant infantile osteopetrosis
(MIOP) which is the autosomal recessive linked form
of the disease. MIOP is the most aggressive form of
the disease, and it is often fatal quite early. 70% of
patients with MIOP will die within the first six years
of their lives. It affects 1 out of every 300,000
newborns. Children often present with short stature
and abnormal heads.
Figure 1. A child with osteopetrosis showing the commonly associated bone
abnormalities. (6)
OSTEOCLASTS
Figure 2. Diagram of a reabsorpting osteoclast with
common osteopetrosis-linked genes marked. (1)
A bone marrow transplant is the most effective
method of treatment for osteopetrosis because it
deals directly with the origin of osteoclasts. Close
matches are ideal, but if the t cells are heavily
suppressed imperfect matches then can work as
well. There is a 70% survival rate with a perfect
match and a 13-45% survival rate for poor matches
(1). Unfortunately there are no curative treatments,
so the only option is to treat the symptoms with
vitamin supplements and blood transfusions. Future
treatments will hope to target the acid processes
that lie at the root of osteopetrosis. Specifically,
gene and cell therapy of hematopoietic stem cells
could be utilized to produce viable osteoclasts or its
precursors for use in medicines (4).
Osteopetrosis arises from inheritance or mutation of
particular osteoblast related genes, which may be
dominant, recessive, or X-linked. The disease exists in two
main forms. The first and most rare form is an issue of
differentiation, usually caused by faulty RANKL signals or
their receptors (RANK) (4). The second form, associated
with MIOP, is much more common and occurs from
recessive inheritance of or failure of at least one of the
following: TCIRG1 (proton pump), CLCN7 (chloride
channel), and OSTM (a transmembrane protein)(1). These
genes are associated with acidification of the ruffled
border. Improper acid production renders the osteoclasts
ineffective at remodeling, leading to severe osteopetrosis
(MIOP in particular). Without existing or functioning
osteoclasts, the remodeling process becomes abnormalosteoblast cells continue to add new bone material, but
no old bone is removed.
Figure 3. (Top): H&E of non-osteopetrotic
bone; (Middle): H&E of rare osteopetrotic
poor condition; (Bottom): osteopetrosis with
dysfunctional osteoclasts presence indicated
by arrows. (2)
Osteoclasts derive from the myeloid hematopoietic
cell line (1) and circulate as a progenitor cell before
entering tissue and completing differentiation.
These cells aid in bone remodeling by removing old
ossified tissue. Osteoclasts may exist in a flat,
motile state or may become a polarized absorptive
cell. When activated, osteoclasts bind to the bone
via vitronectins to create a ruffled zone into which
HCl is secreted. The acid helps to degrade the
hydroxyapatite crystals and Collagen I. The acid
production and secretion relies on many
genes/enzymes including H+ pumps, carbonic
anhydrase II, and chloride channels, and other
proteins.
TREATMENTS
Figure 5. A hepatosplenomegaly CT
scan. Liver on left, spleen on right. (8)
SECONDARY EFFECTS
There are a host of secondary effects associated
with MIOP. The two most potent and damaging are
the excessive growth of bone and the loss of bone
marrow (1). Without working osteoclasts, fetal
woven bone is not successfully remodeled into
lamellar bone, leading to the characteristic dense
but brittle bones associated with the disease. This
expansion of bone interferes with medullary
hematopoiesis causing dangerously low blood cell
levels. Other secondary effects include dental
deformities, extramedullary hematopoiesis that
causes hepatosplenomegaly, reduced cranial space
that indicates hydrocephalus, and hypocalcemia can
develop and cause seizures (3). Nerves can also get
compressed, especially those of the skull’s foramina.
Visual and auditory loss often result of this
compression. It’s possible that nerve atrophy or
hydrocephalus may even cause retardation (5).
Figure 6. Teeth deformities often linked to osteopetrosis. (9)
Figure 4. Cross-section of an
osteopetrotic long bone, displaying
fully-ossified interior sections that
have displaced bone marrow. (7)
Figure 9. X-Ray (left) and
histology (right) of mice with
and without hematopoietic
stem cell therapy. A/E: three
week old control mouse with
much bone marrow; B/F: three
week old untreated
osteopetrotic mouse--note
complete ossification; C/G:
eight week old treated mouse
showing slight improvment;
D/H: eighteen week old
treated mouse demonstrating
control-like bone tissue. (12)
REFERENCES AND ACKNOWLEDGEMENTS
Figure 7. Nonosteopetrotic X-Ray
with average bone
size and density
(11)
Figure 8. X-Ray of
a patient with
osteopetrosis,
clearly showing
the increase in
bone size and
density. (10)
1. Askmyr, Maria K., Anders Fasth, and Johan Richter. “Towards a Better
Understanding and New Therapeutics of Osteopetrosis.” British Journal of
Haematology. (2008) 140.6 597-609.
2. Del Fattore, Andrea, Marta Capannolo, and Anna Teti. “New
Mechanisms of Osteopetrosis.” International Bone and Mineral Society
(2009) 6.1 16-28
3. Srinivasan, Madhusudan, Mario Abinun, Andrew J. Cant, Kelvin Tan,
Anthony Oakhill, and Colin G. Steward. “Malignant infantile osteopetrosis
presenting with neonatal hypocalcemia.” Archives of Disease in
Childhood: Fetal & Neonatal (2000) 83.1 F21-23
4. Stark, Zornitza, and Ravi Savarirayan. “Osteopetrosis.” Orphanet Journal
of Rare Diseases (2009) 4.5 1-12
5. Steward, C. G. “Neurological aspects of osteopetrosis.”
Neuropathology and Applied NeurobiologyI (2003) 29.2 87-97
6.
http://upload.wikimedia.org/wikipedia/commons/3/37/Osteopetrosis_tar
da2.PNG
7. http://www.uwyo.edu/vetsci/undergraduates/courses/patb_4110/46/class_6.jpg
8.
http://images.radiopaedia.org/images/381457/6e170bb3a3db9f0dd82c3
836018f7a.jpg
9. http://www.nature.com/bmt/journal/v29/n6/images/1703416f4.jpg
10. http://www.traumatologiaveterinaria.com/divulgacion/015_03/f4.jpg
11. http://dangalatkenya.blogspot.com/2010/10/knock-knees-andnavicular-bone.htm
12.
http://bloodjournal.hematologylibrary.org/content/109/12/5178.full.pdf
We would like to acknowledge Dr. Blystone for making us do this and
learn any and all of what is above mentioned on bone function.