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Published on: January 12, 2015
Bone Morphogenetic Proteins: Inhibitors of Myelination in Development and Disease
1Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract:
Myelin, the lipid membrane that surrounds axons, is critical for the propagation of nervous impulses and axonal maintenance. The destruction of myelin or lack of myelin formation due to disease or injury causes severe motor and cognitive disability. Regeneration of myelin is theoretically possible but rarely happens. Myelin is synthesized as the plasma membrane of the oligodendrocyte in the central nervous system. During development, myelin and oligodendrocytes are generated from oligodendrocyte progenitors through a process modulated by extrinsic growth factors signaling to cell-intrinsic proteins. Among the key extrinsic factors are the bone morphogenetic proteins (BMPs), potent inhibitors of oligodendrocyte differentiation and myelin protein expression, likely serving to regulate myelination temporally and spatially. BMPs also promote astrocyte generation. Given the inhibitory role of BMP in oligodendrogliogenesis during development, the expression of BMP during demyelinating disease or injury was investigated, as was whether BMP upregulation could serve to prevent regeneration by both direct inhibition of myelination and increases in astrogliosis. BMPs, predominantly BMP4, were increased in animal models of spinal cord injury, stroke, multiple sclerosis, and perinatal white matter injury. A number of studies inhibited BMP signaling by infusing the injury site with the BMP-specific inhibitor noggin or transplanting stem cells engineered to secrete noggin. In most cases, noggin increased the numbers of mature oligodendrocytes and decreased numbers of astrocytes. Some studies also showed functional improvement. BMP is one of several inhibitory growth factors that now appear to inhibit myelin regeneration. Common downstream mechanisms among these factors are likely to be identified.
Insights
Bone morphogenetic proteins (BMPs) inhibit myelin regeneration after injury. Blocking BMP signaling with noggin promotes oligodendrocyte differentiation and astrocyte reduction, aiding myelin repair.
Area of Science:
- Neuroscience
- Cell Biology
- Regenerative Medicine
Background:
- Myelin, essential for nerve impulse propagation and axonal health, is formed by oligodendrocytes in the central nervous system.
- Myelin damage from disease or injury leads to significant motor and cognitive impairments, with limited natural regeneration.
- Oligodendrocyte development and myelination are regulated by extrinsic growth factors, including bone morphogenetic proteins (BMPs).
Purpose of the Study:
- To investigate the role of BMPs in demyelinating diseases and their potential to inhibit myelin regeneration.
- To determine if elevated BMP levels contribute to reduced myelination and increased astrogliosis post-injury.
- To evaluate the therapeutic potential of inhibiting BMP signaling for promoting myelin repair.
Main Methods:
- Analysis of BMP expression in animal models of central nervous system injury and disease (spinal cord injury, stroke, multiple sclerosis, perinatal white matter injury).
- Inhibition of BMP signaling using the BMP-specific inhibitor noggin, delivered via direct infusion or engineered stem cells.
- Assessment of oligodendrocyte differentiation, astrocyte numbers, and functional recovery following BMP inhibition.
Main Results:
- BMPs, particularly BMP4, were found to be upregulated in various animal models of demyelinating conditions.
- Inhibition of BMP signaling with noggin led to increased numbers of mature oligodendrocytes and reduced astrocyte populations.
- Therapeutic intervention targeting BMP signaling demonstrated potential for functional improvement in some studies.
Conclusions:
- Bone morphogenetic proteins (BMPs) are key inhibitors of oligodendrocyte differentiation and myelin regeneration.
- Elevated BMP levels in injury sites likely impede myelin repair by suppressing myelination and promoting astrogliosis.
- Targeting BMP signaling pathways represents a promising therapeutic strategy for enhancing myelin regeneration and functional recovery.
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