However, until recently little was known about the cellular and
molecular mechanisms by which BMPs elicit bone formation. In a series
of stunning studies over the last several years, molecular cell biologists
working intensively in several laboratories have elucidated some
of these mechanisms. When BMPs bind to their cell surface receptors
on mesenchymal cell, a BMP signaling cascade is activated. Signals
are sent via specific proteins to the cell nucleus. This results
in the expression of genes that lead to the synthesis of macromolecules involved
in cartilage and bone formation, and the mesenchymal cell becomes
a chondrocyte or an osteoblast.
The development of knowledge in this area of BMP signal transduction
during the last several years has been phenomenal and has provided
a substantial amount of new information that is clear-cut, specific,
and useful. Some of this new information may be of clinical relevance
because it suggests potential therapeutic approaches to enhance
or suppress new bone formation. Several of the studies on the mechanisms
of BMP signal transduction presented at the International Conference
on Bone Morphogenetic Proteins (held in Lake Tahoe, California,
June 7 through 11, 2000) have been included in this supplement.
In each article, the authors have included in the introductory section
a lucid summary of the development of knowledge in a particular
area.
In the general introduction that follows, the role of bone matrix
as a repository of BMPs is described.
The osteoinductive capacity of BMPs has been demonstrated in
preclinical models, and the efficacy of BMPs for the treatment of
orthopaedic patients is now being evaluated in clinical trials
4-6,11,14-16,40,55
. The clinical applications of recombinant BMP-2 and BMP-7 (also
known as osteogenic protein-1 [OP-1]) are being studied most extensively.
Friedlaender et al. carried out a clinical trial of the efficacy
of OP-1 in the treatment of tibial nonunions, and an article describing
their results is included in part 2 of this supplement.
At the end of the session on "Clinical Applications of the BMPs
in Orthopaedic Surgery" at this conference, a discussion followed
that focused on unresolved issues related to the use of the BMPs
in the treatment of problem fractures and nonunions. The question
was raised, "What should be the design of clinical trials to demonstrate
the efficacy of the BMPs in the treatment of problem fractures and
nonunions?" Several participants addressed this question. Their
thoughts and some guidelines for the design of clinical trials are
presented in the Commentary section at the end of this issue. Concerns
were expressed as to whether carrier and delivery systems with requisite
properties, which adequately immobilize the growth factor and release
it with desirable kinetics, will be used in the treatment of orthopaedic
patients.
It was suggested that further progress in the clinical application
of the BMPs will depend upon the development of carriers with ideal
release kinetics for the delivery of the BMPs. In the section entitled "Delivery
Systems for the BMPs" in part 2 of this supplement, articles are
included that describe the preparation of new carriers
23,29,40
with defined BMP-release kinetics. These carriers may yield even
better results in experimental models of the osteoinductive effects
of the BMPs and in clinical trials.
Note: I wish to thank Mrs. Rita Rowlands for her truly outstanding
help in the preparation of this manuscript and the references. This
work was supported by the Lawrence J. Ellison Chair in Musculoskeletal
Molecular Biology.