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Faculty Ernst Reichenberger
Assistant Professor of Oral Rehabilitation, Biomaterials and
Skeletal Development, Center for Regenerative Medicine and Skeletal
Development
reichenberger@uchc.edu
Keywords:
- aplasia cutis congenita (ACC)
- bone
- cherubism
- craniofacial biology
- craniometaphyseal dysplasia (CMD)
- keloids
- molecular genetics
- skin
- wound healing
Areas of Interest:
The skin and skeleton would seem to be very stable parts of the human
body. Contrary to appearances, however, both skin and skeleton are in a
nearly constant state of flux. The bone mass in skeletal structures is
the result of a shifting balance between bone formation and bone
resorption, while the skin is constantly sloughed and often subjected to
injuries, which must rapidly be repaired. The Reichenberger laboratory
is interested in learning about the complex processes required for
generating and maintaining the skin and bones. To find out how the
mechanisms operate in a healthy person, we study human genetic disorders
in which they are disrupted.
In the Reichenberger laboratory, we are interested in dermal and
skeletal development and homeostasis. We are currently studying three
specific human genetic disorders where mutations in as yet unidentified
genes interrupt the normal cellular pathways governing these processes,
leading to abnormal tissue behavior. Through the use of human linkage
analyses, we aim to identify the genes involved in each disorder.
The selection of the disorders like keloid formation,
craniometaphyseal dysplasia (CMD), and cherubism (CBM), was guided by
our interest in extracellular matrix regulation, skeletogenesis, and
bone homeostasis. These diseases can be passed on in autosomal dominant
or recessive modes and can also occur sporadically. Collecting affected
families and verifying the diagnosis of family members has required a
substantial effort, as penetrance and expressivity are variable in all
these diseases, and the bone disorders, in particular, are very rare.
Keloids:
Injured skin regenerates via a complex wound healing mechanism that
leads to scar formation. Keloids are formed when scar tissue does not
stop growing but continues to expand over the original margin of the
wound like a tumor. In affected families, the tendency to form keloids
is an inherited disorder. Once we have identified the genes responsible
for heritable keloid formation and identified the mutations, we will be
able to study the functions of these genes and the biological
consequences of mutations. Our long-term objective is to use keloid
formation as a model to examine the molecular mechanisms leading to
neoformation of dermal tissue in fibrotic diseases, as well as in normal
wound healing.
Bone Formation Disorders:
The goals for the bone projects are to elucidate molecular mechanisms
regulating craniofacial bone formation and homeostasis. The level of
bone mass in every skeletal structure reflects a balance between bone
formation by osteoblasts and bone resorption by osteoclasts.
Craniometaphyseal dysplasia (CMD) is a rare genetic disorder in which
metaphyses of long bones are flared and reveal decreased bone density.
Cranial bones show striking overgrowth and increased density of bone.
The opposite effect is observed in cherubism (CBM). CBM is a disorder of
age-related bone remodeling that is limited to the maxilla and the
mandible. During childhood, increased osteoclastogenesis leads to loss
of bone in the jaws and replacement of bone with large amounts of
fibrous tissue that keeps proliferating like a tumor. Patients with CBM
show symmetrical hard, but painless, swelling of the jaws. The
involvement of the infraorbital rim and the orbital floor leads to an
upward tilting of the eyes, giving a child the appearance of a
Renaissance cherub.
We have recently identified the genes for the autosomal dominant
forms of cherubism and CMD.
In cherubism, excessive bone resorption and the characteristic
tumor-like growth of proliferating tissue with excessive extracellular
matrix deposition are caused by a mutation in a small signal
transduction molecule, SH3BP2. We currently study the function of this
molecule in order to determine why signals that come into certain bone
cells of the jaws get misdirected and cause the cells to do things they
are not normally supposed to do. In CMD, the protein ANK, which sits in
the cell membrane of bone forming cells is mutated, which apparently
results in a lessened ability to shuttle certain small molecules
(pyrophosphates) out of cells into the surrounding bone matrix. We know
from other models that changes of pyrophosphate levels in the
extracellular matrix cause abnormal bone density. A decrease of
pyrophosphate in the bone matrix causes the bone to become harder than
normal and prevents it from being remodeled by bone resorbing cells (osteoclasts).
We do not yet understand why this CMD gene mutation affects mainly bones
of the face and skull.
Future Directions:
Our immediate goal is to study the biological functions of ANK and
SH3BP2 on a biochemical and cell biological level. Effects of mutations
on upstream and downstream reaction partners of these genes will be
investigated and tested in vivo in animal models and in vitro
in cell culture and organ culture model systems. For the keloid project
we are actively recruiting more families to participate in the study in
order to identify genes that cause keloid formation. Once such genes are
found, we will study the impact of the mutations in scar formation
during normal wound healing and in keloids.
Lab Rotation Projects:
We have created mouse models for the human bone disorders cherubism (OMIM
#118400) and craniometaphyseal dysplasia (OMIM #123000). These models
are currently being analyzed morphologically, histologically, by
micro-CT, and on a molecular level. Projects currently available include
the skeletal analysis of both models. The cherubism model, especially,
has a severe bone phenotype. We also investigate properties of bone
marrow stromal cells and osteoblasts in the cherubism mouse. In summary,
we isolate cells from bone marrow or calvaria, differentiate them into
osteoblasts, and perform various cell culture assays, Northern blot,
cell sorting.
Other projects involve mutation analysis in genomic DNA from patients
with skeletal disorders.
Selected Publications:
Islam M, Lurie AG, and Reichenberger E (2005) Clinical features of
Tricho-Dento-Osseous syndrome and presentation of three new cases: an
addition to clinical heterogeneity. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod (in press).
Jafarov T, Ferimazova N, and Reichenberger E (2005) Noonan-like Syndrome
/ cherubism patients with mutations in PTPN11 Clin Genet (submitted).
Genome Scans provide evidence for keloid susceptibility loci on
chromosomes 2q23 and 7p11. (2004) Marneros AM, Norris JEC, Watanabe S,
Reichenberger E, Olsen BR Investigative J. of Dermatology
122(5):1126-32.
Activation of NF-kB Signal Pathways in Keloid Fibroblasts. (2004)
Messadi D, Doung HS, Zhang Q, Kelly AP, Tuan TL, Reichenberger E, and Le
AD. Arch Dermatol Res. 2004 Aug; 296(3):125-33.
Ueki Y, Tiziani V,Santanna C, Maulik C, Garfinkle J, Ninomiya C,
doAmaral C, Peters H, Habal M, Rhee-Morris L, Doss JB, Kreiborg S, Olsen
BR, and Reichenberger E (2001) Mutations in the c-Abl- binding protein
SH3BP2 cause excessive bone degradation in cherubism. Nature Genetics
28(2):125-126.
Reichenberger E, Tiziani V, Watanabe S, Park L, Ueki Y, Santanna C,
Baur S, Shiang R, Grange DK, Beighton P, Lidral A, Gorlin RJ, Raposo
doAmaral C, Mulliken JB, and Olsen BR (2001) Autosomal dominant
craniometaphyseal dysplasia (CMD) is caused by mutations in the
transmembrane protein ANK. Am J Hum Genet 68(6):1321-1326. |
