Bone Remodeling and Repair

Bone Health in the Balance
Paula Kiberstis, Orla Smith, Colin Norman

Passage through puberty usually signals a halt in bone growth. But bone tissue in adults is not dormant--our bones are continuously being remodeled through repeated cycles of destruction and rebuilding. By some estimates, this remodeling process is so extensive that it completely regenerates the adult skeleton every 10 years. * Remodeling most likely serves a repair function, especially in bones subjected to mechanical stress.

In healthy young adults, the amount of new bone formation approximately balances the amount of bone destruction (resorption). As we age, however, the balance shifts to favor bone resorption, which can result in debilitating diseases such as osteoporosis. In the United States alone, about 10 million people have been diagnosed with this disease, with attendant medical costs exceeding $14 billion per year. Another 18 million people have low bone mass, putting them at increased risk for the disease.

This special issue of Science reviews recent advances in our understanding of the cell and molecular biology of bone remodeling and how these advances are being applied to the development of new therapeutics. Remodeling depends on the tightly integrated activity of two major cell types: the osteoblasts, which make new bone, and the osteoclasts, which destroy old bone. As discussed by Ducy et al., many important insights into osteoblast function have come from studies of genetically defined mouse models. In addition to providing fundamental information about the transcription factor networks that govern osteoblast differentiation, mouse models were instrumental in the discovery of a centrally acting regulatory pathway for bone mass, a key mediator of which is leptin, a hormone already famous for its role in body weight regulation. Teitelbaum describes the signaling molecules that control bone resorption by osteoclasts, including a soluble receptor called osteoprotegerin, whose identification 3 years ago considerably clarified our understanding of how osteoblasts and osteoclasts communicate.

The good news is that the balancing act intrinsic to bone remodeling presents researchers with two general intervention points for preventing and treating bone disease. Rodan and Martin discuss the wealth of available drugs (estrogens, selective estrogen receptor modulators, and bisphosphonates) that act by blocking osteoclast activity and bone resorption. Less well explored, but a potentially valuable adjunct therapy, are agents that promote osteoblast activity and bone formation, such as statins.

In a News story, Service discusses recent efforts to repair broken and diseased bone through tissue engineering. Clinical trials are being planned, and in some cases are already under way, to encourage bone regrowth using novel matrices that provide a molecular scaffolding for new osteoblasts, implantation of signaling molecules or cultured stem cells at the repair site, and even gene therapy. Commercial interest is high, and some scientists worry that intellectual property claims could hinder progress.

Delicate as osteoblasts and osteoclasts may appear to be under the microscope, their robust and unceasing activities imbue us with the mechanical prowess to climb mountains or run marathons. Finding ways to reinstate their balance is a finish line worth striving for.

* S. C. Manolagas, Endocrine Rev. 21, 115 (2000).

Tissue Engineers Build New Bone
Science 2000 289: 1498-1500.
Robert F. Service

Bone repair may be one of the first major applications of tissue engineering; efforts to encourage the growth of new bone using novel matrices, bone morphogenic proteins, gene therapy, and stem cells are all showing promise. But the commercial stakes are so high that some researchers are worried that patent claims, and a reluctance to test competing technologies in combination, could delay progress in the field.

The Osteoblast: A Sophisticated Fibroblast under Central Surveillance
Science 2000 289: 1501-1504.
Patricia Ducy, Thorsten Schinke, Gerard Karsenty*
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

The study of the biology of osteoblasts, or bone-forming cells, illustrates how mammalian genetics has profoundly modified our understanding of cell differentiation and physiologic processes. Indeed, genetic-based studies over the past 5 years have revealed how osteoblast differentiation is controlled through growth and transcription factors. Likewise, the recent identification, using mutant mouse models, of a central component in the regulation of bone formation expands our understanding of the control of bone remodeling. This regulatory loop, which involves the hormone leptin, may help to explain the protective effect of obesity on bone mass in humans. In addition, it provides a novel physiologic concept that may shed light on the etiology of osteoporosis and help to identify new therapeutic targets.

Bone Resorption by Osteoclasts
Science 2000 289: 1504-1508.
Steven L. Teitelbaum
Department of Pathology, Washington University School of Medicine, Barnes-Jewish Hospital North, Mailstop 90-31-649, 216 South Kingshighway, St. Louis, MO 63110, USA.

Osteoporosis, a disease endemic in Western society, typically reflects an imbalance in skeletal turnover so that bone resorption exceeds bone formation. Bone resorption is the unique function of the osteoclast, and anti-osteoporosis therapy to date has targeted this cell. The osteoclast is a specialized macrophage polykaryon whose differentiation is principally regulated by macrophage colony-stimulating factor, RANK ligand, and osteoprotegerin. Reflecting integrin-mediated signals, the osteoclast develops a specialized cytoskeleton that permits it to establish an isolated microenvironment between itself and bone, wherein matrix degradation occurs by a process involving proton transport. Osteopetrotic mutants have provided a wealth of information about the genes that regulate the differentiation of osteoclasts and their capacity to resorb bone.

Therapeutic Approaches to Bone Diseases
Science 2000 289: 1508-1514.
Gideon A. Rodan,1* T. John Martin2
1 Merck Research Laboratories, West Point, PA 19486, USA.
2 St. Vincent's Institute of Medical Research, Melbourne 3065, Australia.

The strength and integrity of our bones depends on maintaining a delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. As we age or as a result of disease, this delicate balancing act becomes tipped in favor of osteoclasts so that bone resorption exceeds bone formation, rendering bones brittle and prone to fracture. A better understanding of the biology of osteoclasts and osteoblasts is providing opportunities for developing therapeutics to treat diseases of bone. Drugs that inhibit the formation or activity of osteoclasts are valuable for treating osteoporosis, Paget's disease, and inflammation of bone associated with rheumatoid arthritis or periodontal disease. Far less attention has been paid to promoting bone formation with, for example, growth factors or hormones, an approach that would be a valuable adjunct therapy for patients receiving inhibitors of bone resorption.