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Specific Blockade of Bone Morphogenetic Protein-2/4 Induces Oligodendrogenesis and Remyelination in Demyelinating
Karin Mausner-Fainberg1, Moshe Benhamou1,2, Maya Golan1
1Neuroimmunology Laboratory, Neuroimmunology and Multiple Sclerosis Unit, Neurology Division, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 6423906, Tel Aviv, Israel.
Abstract:
Oligodendrocyte precursor cells (OPCs) are present in demyelinated lesions of multiple sclerosis (MS) patients. However, their differentiation into functional oligodendrocytes is insufficient, and most lesions evolve into nonfunctional astroglial scars. Blockade of bone morphogenetic protein (BMP) signaling induces differentiation of OPCs into myelin-producing oligodendrocytes. We studied the effect of specific blockade of BMP-2/4 signaling, by intravenous (IV) treatment with anti-BMP-2/4 neutralizing mAb in both the inflammatory model of relapsing experimental autoimmune encephalomyelitis (R-EAE) and the cuprizone-toxic model of demyelination in mice. Administration of anti-BMP-2/4 to R-EAE-induced mice, on day 9 post-immunization (p.i.), ameliorated R-EAE signs, diminished the expression of phospho-SMAD1/5/8, primarily within the astrocytic lineage, increased the numbers of de novo immature and mature oligodendrocytes, and reduced the numbers of newly generated astrocytes within the spinal cord as early as day 18 p.i. This effect was accompanied with elevated remyelination, manifested by increased density of remyelinating axons (0.8 < g-ratios < 1), and reduced fully demyelinated and demyelinating axons, in the anti-BMP-2/4-treated R-EAE mice, studied by electron microscopy. No significant immunosuppressive effect was observed in the CNS and in the periphery, during the peak of the first attack, or at the end of the experiment. Moreover, IV treatment with anti-BMP-2/4 mAb in the cuprizone-challenged mice augmented the numbers of mature oligodendrocytes and remyelination in the corpus callosum during the recovery phase of the disease. Based on our findings, the specific blockade of BMP-2/4 has a therapeutic potential in demyelinating disorders such as MS, by inducing early oligodendrogenesis-mediated remyelination in the affected tissue.
Insights
Blocking bone morphogenetic protein-2/4 (BMP-2/4) with an antibody promotes oligodendrocyte precursor cell differentiation. This treatment enhances remyelination and shows therapeutic potential for demyelinating diseases like multiple sclerosis (MS).
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Multiple sclerosis (MS) involves demyelination, where oligodendrocyte precursor cells (OPCs) fail to differentiate, leading to glial scarring.
- Bone morphogenetic protein (BMP) signaling inhibits OPC differentiation into myelin-producing oligodendrocytes.
- Targeting BMP signaling offers a potential strategy to promote remyelination in demyelinating diseases.
Purpose of the Study:
- To investigate the therapeutic potential of blocking BMP-2/4 signaling in experimental models of demyelination and neuroinflammation.
- To assess the impact of anti-BMP-2/4 antibody treatment on oligodendrocyte differentiation, remyelination, and glial scarring.
Main Methods:
- Intravenous administration of anti-BMP-2/4 neutralizing monoclonal antibody (mAb) in mice with relapsing experimental autoimmune encephalomyelitis (R-EAE) and cuprizone-induced demyelination.
- Assessment of clinical signs, phospho-SMAD1/5/8 expression, oligodendrocyte and astrocyte populations, and axonal integrity using histology and electron microscopy.
- Evaluation of potential immunosuppressive effects in the central nervous system (CNS) and periphery.
Main Results:
- Anti-BMP-2/4 treatment ameliorated R-EAE signs, reduced astrogliosis, and increased immature and mature oligodendrocyte numbers.
- Enhanced remyelination was observed, with increased density of remyelinating axons and reduced demyelinated axons in treated mice.
- No significant immunosuppressive effects were detected; treatment also promoted remyelination in the cuprizone model during recovery.
Conclusions:
- Specific blockade of BMP-2/4 signaling promotes oligodendrogenesis and remyelination in demyelinating conditions.
- Anti-BMP-2/4 antibody treatment demonstrates therapeutic potential for treating demyelinating disorders like MS.
- This approach facilitates endogenous repair mechanisms by enhancing OPC differentiation and myelin regeneration.
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