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Refined Murine Model of Idiopathic Pulmonary Fibrosis
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Rescue of a primary myelofibrosis model by retinoid-antagonist therapy
Suk-Hyun Hong1, Melita Dvorak-Ewell, Hazel Y Stevens
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
Abstract:
Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-β and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression.
Insights
Targeting the SMRT-retinoic acid receptor interaction in mice caused skeletal issues and primary myelofibrosis. Retinoid antagonists reversed these effects, offering a potential therapeutic target for myelofibrosis.
Area of Science:
- Molecular biology
- Epigenetics
- Hematology
Background:
- Primary myelofibrosis is a chronic, often idiopathic disorder with high morbidity and mortality.
- Current treatments for myelofibrosis are largely palliative.
- The role of the silencing mediator of retinoid and thyroid hormone receptors (SMRT) in myelofibrosis is not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying SMRT-induced primary myelofibrosis.
- To identify potential therapeutic targets for blocking myelofibrosis progression.
Main Methods:
- Molecular targeting of SMRT receptor interaction domains in mice.
- Analysis of skeletal phenotypes, bone marrow fibrosis, and gene expression.
- Investigating the role of thrombopoietin (Tpo) and its signaling pathway.
Main Results:
- Targeting SMRT induced a skeletal syndrome with reduced bone growth and increased osteoclasts.
- SMRT-targeted mice developed spontaneous primary myelofibrosis.
- Thrombopoietin (Tpo) was identified as a key target in the SMRT-retinoic acid receptor pathway, leading to fibrosis.
- Retinoid antagonists rescued the myelofibrosis syndrome in mice.
Conclusions:
- The physical interface between SMRT and retinoic acid receptor is a critical driver of primary myelofibrosis.
- Blocking this interaction with retinoid antagonists represents a promising therapeutic strategy for myelofibrosis.
