Background: The formation of the skeleton requires inductive signals
that are balanced with their antagonists in a highly regulated negative
feedback system. Inappropriate or excessive expression of BMPs (bone
morphogenetic proteins) or their antagonists results in genetic disorders
affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP
signaling mediated through binding to its receptors is a critical step in the
induction of abnormal ossification. Therefore, we hypothesized that
engineering more effective inhibitors of this BMP-signaling process may lead
to the development of therapies for such conditions.
Methods: BMP4-induced heterotopic ossification was used as a model
for testing the ability of the BMP antagonist Noggin to block de novo bone
formation, either by local or systemic delivery. Since Noggin naturally acts
locally, a Noggin mutein, hNOG?B2, was engineered and was shown to
circulate systemically, and its ability to block heterotopic ossification was
tested in a mouse model with use of adenovirus-mediated somatic cell gene
transfer.
Results: A mouse model of BMP4-induced heterotopic ossification was
developed. Local delivery of wild-type NOG inhibited heterotopic ossification,
but systemic administration was ineffective. In contrast, systemic delivery of
the adenovirus encoding hNOG?B2 resulted in systemic levels that
persisted for more than two weeks and were sufficient to block BMP4-induced
heterotopic ossification.
Conclusions: BMP4-induced heterotopic ossification can be prevented
in vivo either by local delivery of wild-type Noggin or after somatic cell
gene transfer of a Noggin mutein, hNOG?B2. Furthermore, the data in the
present study provide proof of concept that a naturally occurring factor can
be engineered for systemic delivery toward a desirable pharmacological
outcome.
Clinical Relevance: Blocking bone formation is clinically relevant
to disorders of heterotopic ossification in humans, such as fibrodysplasia
ossificans progressiva. Furthermore, development of BMP antagonists as
therapeutic agents may provide modalities for the treatment of other
pathologic conditions that arise from aberrant expression of BMPs and/or from
a lack of their antagonists.