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
Article: Osteoclast differentiation and
Journal: NATURE, 423 (6937): 337-342 MAY 15 2003
Addresses: Prot Pathways Inc, Woodland Hills, CA 91367
Amgen Inc, Thousand Oaks, CA 91320 USA.
Prot Pathways Inc, Woodland Hills, CA 91367 USA.
Why do you think your paper is highly
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
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?
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
Where do you see your research leading in the
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
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.