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, they 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 several specific human genetic disorders. For some disorders we have identified disease genes while search for new genes in other disorders. Disease genes interrupt the normal cellular pathways governing developmental and tissue remodeling processes, leading to abnormal tissue behavior.

The selection of disorders like keloid formation, craniometaphyseal dysplasia (CMD), aplasia cutis congenital (ACC) 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 requires 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. We use Linkage Analysis and Association Studies (GWAS) to identify keloid genes. 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. Maintaining 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 in symmetrical lesions and replacement of bone with large amounts of fibrous tissue that keeps proliferating like a tumor and can lead to severe swelling of the jaws. Children born with aplasia cutis congenita (ACC) have absent or very thin skin, usually on the scalp. Sometimes the underlying bone is affected as well. ACC can be inherited or appear spontaneously, supposedly by de-novo mutations.

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. In CMD, mutations in the ANKH protein are responsible for the disorder. The transmembrane protein ANKH is known to transport pyrophosphate out of cells and possibly has additional functions. ANKH is a regulator of bone mineralization and possibly prevents mineralization in all other tissues. The ANKH mutations have a profound effect on the function of osteoblasts and osteoclasts but 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 as well as for the bone projects we are actively recruiting more patients to participate in the study in order to identify new genes that cause disorders.

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