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David Lacey & Scott Simonet talk with ScienceWatch.com and answer a few questions about this month's Fast Moving Front in the field of Molecular Biology & Genetics. The authors have also sent along images of their work.

Article: Osteoclast differentiation and activation
Authors: Boyle, WJ;Simonet, WS;Lacey, DL
Journal: NATURE, 423 (6937): 337-342 MAY 15 2003
Addresses: Prot Pathways Inc, Woodland Hills, CA 91367 USA.
Amgen Inc, Thousand Oaks, CA 91320 USA.
Prot Pathways Inc, Woodland Hills, CA 91367 USA.
 

  Why do you think your paper is highly cited?


Coauthor
Scott Simonet 


Coauthor
William Boyle

This paper was an invited review article that summarized, circa 2003, what was known in the field of osteoclast differentiation. There had been an explosion of insights in the field over the previous decade and this article succinctly summarized the current state of knowledge with the focus on the central importance of the RANK Ligand pathway.

  Does it describe a new discovery, methodology, or synthesis of knowledge?

As this was a review article, the publication was a synthesis of knowledge of the field. It was clear by the time that this article was published that the newly characterized signaling pathway, the RANKL (Receptor Activator for Nuclear Factor ? B Ligand) pathway, was essential to all aspects of osteoclast biology. This article was written to integrate the RANKL pathway with the other known pathways, hormones, and cells known to play a role in osteoclast biology.

  Would you summarize the significance of your paper in layman's terms?

Excess bone resorption occurs across a spectrum of diseases that affect many millions of people worldwide. These would include postmenopausal osteoporosis, cancer-related bone disease, rheumatoid arthritis, and others. The body’s cells that actually dissolve the bony tissue are called osteoclasts. The cells develop from immature cells that come from the bone marrow.

This paper describes the factors that govern the development of the bone-resorbing cells from their bone marrow progenitors. The recent discovery of the RANKL pathway represents an important landmark because we now understand a seminal pathway that provides the basis for further research as well as a fundamental rationale for new drug development.

  How did you become involved in this research and were there any particular problems encountered along the way?

Figure 1: + details
Click figure to enlarge and read description.

The authors worked together at Amgen in the mid '90s and discovered osteoprotegerin, the first member of the RANK ligand pathway to be described, and subsequently defined the biology of the other two members (RANK and RANK ligand). The big break in the field for us was the phenotype of the osteoprotegerin (OPG) transgenic mouse that highlighted OPG's central relevance to osteoclast biology. Subsequent efforts were focused on finding the other related members of this pathway. There was intense competition during the latter '90s between the authors and investigators in both industry and academia. The discovery of this pathway and the availability of reagents led to an explosion of knowledge about osteoclast biology.

  Where do you see your research leading in the future?

There are two major thrusts that research will lead to in the future. In the area of novel therapeutics for bone loss conditions, Amgen is currently in late-stage clinical trials with a fully human monoclonal antibody directed against RANKL termed "denosumab." And research continues into other aspects of osteoclast biology that are now possible to do given reagent availability.

  Do you foresee any social or political implications for your research?

Denosumab has the potential to be a new therapeutic approach for patients with a variety of bone loss conditions. More than 19,000 patients around the world are currently involved in registrational studies necessary to obtain FDA approval for denosumab.

David Lacey, M.D.
Amgen Senior Vice President of Research
Thousand Oaks, CA, USA

Scott Simonet, Ph.D.
Amgen Executive Director of Research
Thousand Oaks, CA, USA

Keywords: osteoclast differentiation, RANK Ligand pathway, RANKL, Receptor Activator for Nuclear Factor B Ligand, RANKL pathway, osteoclast biology, osteoclasts, bone resorption, postmenopausal osteoporosis, cancer-related bone disease, rheumatoid arthritis, Amgen, osteoprotegerin, OPG, transgenic mouse, Denosumab.

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2008 : July 2008 - Fast Moving Fronts : David Lacey & Scott Simonet