What holds us together? Why do some of us fall apart? What can we do about it?

One of the intriguing questions about complex organisms is, What holds them together? One of the principal answers is the tough, fibrous material known as collagen. A related question is, How is collagen made? The biosynthesis of the protein has several unusual features. One is the extensive use of the principle of spontaneous self-assembly seen in the formation of crystals. The three polypeptide chains of the protein fold into a triple-helical conformation by a process that begins with the formation of a small nucleus of triple helix at the C-terminus of the molecule and then propagation of the nucleus in a zipper-like fashion. Also, the self-assembly of the collagen monomers into fibrils is an entropy driven, crystallization-like process. Why do some of them fall apart? Mutations that alter the expression or primary structure of collagen are the predominant causes of severe skeletal defects such as osteogenesis imperfecta and chondrodysplasias. Mutations that have milder effects on the synthesis or structure of the protein are found in a subset of patients with more common diseases such as osteoporosis and early onset osteoarthritis. What can we do about the defects in collagen? Recent results have emphasized the importance of earlier observations that bone marrow contains a small subset of cells that are progenitors of osteoblasts, chondroblasts and several other types of nonhematopoietic cells. After systemic infusion into irradiated mice, the infused cells slowly replace a small fraction of the cells in bone, cartilage, lung and several other tissues. Therefore, the results suggest that the cells, known as mesenchymal stem cells or marrow stromal cells, can be used for both cell and gene therapy of diseases in which bone, cartilage and other connective tissues fall apart.