National Institute of Arthritis and Musculoskeletal and Skin Diseases

For Immediate Release
Wednesday, December 4, 2002 

Contact: Judith Wortman 
Office of Communications 
and Public Liaison 
(301) 496-8190

Eight new research grants funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) will shed light on heritable diseases of connective tissue. The new grant awards support individual research projects as well as collaborative exploratory and developmental grants that investigate the cause of one or more of these disorders and novel treatment pathways. NIAMS is a component of the National Institutes of Health (NIH) within the U.S. Department of Health and Human Services.

Heritable disorders of connective tissue are rare diseases that result from mutations in genes responsible for building tissues. Disorders of connective tissue - the material between cells that gives tissues form and strength - include such conditions as osteogenesis imperfecta and Ehlers-Danlos syndrome, and, in total, may affect as many as a million people in the United States.

"We are pleased with the quality of research that has been proposed in response to the Request for Applications," says NIAMS Director Stephen I. Katz, M.D., Ph.D. "We need to understand more about these disorders and how they can be effectively treated, and I believe these eight research projects are an important step in that direction."

The Request for Applications (RFA) was issued in response to recommendations made at the Third Workshop on Heritable Disorders of Connective Tissue that was held at NIH in November 2000 and sponsored by NIAMS, the NIH Office of Rare Diseases, and several nonprofit organizations outside NIH. In addition to the NIAMS grants, several grants have been awarded by the National Heart, Lung and Blood Institute, another component of NIH and a co-sponsor of the RFA.

Heritable connective tissue disorders in humans are associated with many mutations that affect connective tissue proteins, including over 300 mutations affecting collagen, a protein substance found in skin, bone, cartilage, and all other connective tissues. Researchers supported by these grants will study the functions of connective tissue proteins and how mutations result in disease. Following is a brief description of each grant.

Role of ADAMTS-3 in Procollagen Processing , Suneel S. Apte, Cleveland Clinic, Ohio. ADAMTS-3 is a procollagen processing enzyme responsible for ensuring formation of mature collagen. Studying transgenic mice where the ADAMTS-3 gene is inactivated may provide clues for identifing novel connective tissue disorders and for treating a subtype of Ehlers-Danlos syndrome, which is characterized by severe skin fragility.

Genetics of Sagg: A Heritable Mouse Model for Cutis Laxa , Paul J. Christner, Thomas Jefferson University, Philadelphia, Pennsylvania. Cutis laxa is a connective tissue disease characterized by sagging skin, premature wrinkling and reduced skin elasticity. The researcher will investigate the Sagg mouse, which has these symptoms, as a potential model for studying the molecular mechanisms of cutis laxa.

Collagen-Proteoglycan Interactions in Connective Tissue Disorders , James D. San Antonio, Thomas Jefferson University, Philadelphia, Pennsylvania. Proteoglycans are substances found on type I collagen fibrils (minute fibers) in various tissues. Their interaction with type I collagen may regulate the structure of tissue matrix. The researcher will study whether disruption of this interaction leads to connective tissue disorders.

The Role of Sedlin in Maintaining Cartilage Integrity , George E. Tiller, Vanderbilt, University, Nashville, Tennessee. Spondyloepiphyseal dysplasia tarda (SEDL) is a bone disorder, characterized by short stature and early-onset osteoarthritis. Although the SEDL gene has been identified, little is known about sedlin, the gene product. The researcher will study the role of sedlin in maintaining cartilage and its deterioration in osteoarthritis.

Targeted Mouse Models for Studying Skeletal Dysplasia , Michael D. Briggs, Victoria University of Manchester, England. The researcher will study three forms of genetic disorders of bone development that can result from mutations in two different cartilage structural proteins. Using current technology on mouse models, he will study the molecular, cellular, and extracellular matrix changes that occur in these disorders.

Altered Matrix Cells and Intermolecular Interactions , Andrzej Fertala, Thomas Jefferson University, Philadelphia, Pennsylvania. The researcher will use chondrocytes (cartilage cells) and collagen II in a matrix to test the hypothesis that mutations in fibrillar collagens affect extracellular and intracellular interaction of proteins with other molecules, alter the extracellular matrix, and change the spatial arrangement of cells.

Control of Bone Formation in Craniometaphyseal Dysplasia , Ernst J. Reichenberger, University of Connecticut School of Medicine and Dentistry, Farmington. The protein ANK is responsible for a form of craniometaphyseal dysplasia (CMD), a rare bone disorder characterized by increased craniofacial bone deposition and decreased bone deposition in the metaphyses (the wider portion of long bones that is the growth zone). This study will investigate ANK's molecular properties and its interaction with other proteins.

Pathogenesis of Laminin-alpha2 Deficiency , Jeffrey B. Miller, Boston Biomedical Research Institute, Watertown, Massachusetts. Mutations in the LAMA2 gene cause a form of congenital muscular dystrophy, CMD1. The researcher will use a mouse model to determine how loss of laminin-alpha 2, an extracellular protein that is abundant in skeletal muscle and motor neurons, leads to severe neuromuscular dysfunction.

For more information on heritable disorders of connective tissue, contact:

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 
1 AMS Circle 
Bethesda, MD 20892-3675 
Phone: 301-495-4484 or 
877-22-NIAMS (226-4267) (free of charge) 
TTY: 301-718-6366 
Fax: 301-718-6366 

Coalition for Heritable Disorders of Connective Tissue 
4301 Connecticut Avenue, N.W., Suite 404 
Washington, DC 20008 
Phone: (202) 362-9599 

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a component of the U.S. Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases.

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