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. |
