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Methyl-Beta-Cyclodextrin Restores Aberrant Bone Morphogenetic Protein 2-Signaling in Bone Marrow Stromal Cells
Daniel Halloran1, Venu Pandit1, Kelechi Chukwuocha1
1Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
Abstract:
During aging, disruptions in various signaling pathways become more common. Some older patients will exhibit irregular bone morphogenetic protein (BMP) signaling, which can lead to osteoporosis (OP)-a debilitating bone disease resulting from an imbalance between osteoblasts and osteoclasts. In 2002, the Food and Drug Administration (FDA) approved recombinant human BMP-2 (rhBMP-2) for use in spinal fusion surgeries as it is required for bone formation. However, complications with rhBMP-2 arose and primary osteoblasts from OP patients often fail to respond to BMP-2. Although patient samples are available for study, previous medical histories can impact results. Consequently, the C57BL/6 mouse line serves as a valuable model for studying OP and aging. We find that BMP receptor type Ia (BMPRIa) is upregulated in the bone marrow stromal cells (BMSCs) of 15-month-old mice, consistent with prior data. Furthermore, conjugating BMP-2 with Quantum Dots (QDot®s) allows effective binding to BMPRIa, creating a fluorescent tag for BMP-2. Furthermore, after treating BMSCs with methyl-β-cyclodextrin (MβCD), a disruptor of cellular endocytosis, BMP signaling is restored in 15-month-old mice, as shown by von Kossa assays. MβCD has the potential to restore BMPRIa function, and the BMP signaling pathway offers a promising avenue for future OP therapies.
Insights
Aging disrupts bone morphogenetic protein (BMP) signaling, contributing to osteoporosis. Methyl-β-cyclodextrin (MβCD) restores BMP signaling in aged mice, offering a potential therapeutic strategy for bone disease.
Area of Science:
- Biomedical Science
- Cell Biology
- Aging Research
Background:
- Aging is associated with disrupted signaling pathways, including bone morphogenetic protein (BMP) signaling.
- Osteoporosis (OP) is a bone disease caused by an imbalance between osteoblasts and osteoclasts, often linked to impaired BMP signaling in older individuals.
- Recombinant human BMP-2 (rhBMP-2) is used for bone formation but faces complications, and patient-derived cells may have confounding medical histories, necessitating reliable animal models like C57BL/6 mice.
Purpose of the Study:
- To investigate the role of BMP receptor type Ia (BMPRIa) in aging-related bone marrow stromal cells (BMSCs).
- To develop a method for tracking BMP-2 binding to BMPRIa.
- To explore potential therapeutic interventions for restoring BMP signaling in aged BMSCs.
Main Methods:
- Upregulation of BMPRIa in BMSCs from 15-month-old C57BL/6 mice was assessed.
- BMP-2 was conjugated with Quantum Dots (QDots) to create a fluorescent tag for binding to BMPRIa.
- BMSCs were treated with methyl-β-cyclodextrin (MβCD) to disrupt endocytosis, and BMP signaling restoration was evaluated using von Kossa assays.
Main Results:
- BMP receptor type Ia (BMPRIa) was found to be upregulated in BMSCs of aged mice.
- Conjugation of BMP-2 with QDots enabled effective binding to BMPRIa, serving as a fluorescent marker.
- Treatment with MβCD restored BMP signaling in aged BMSCs, as evidenced by positive von Kossa staining.
Conclusions:
- BMPRIa upregulation in aged BMSCs is confirmed.
- QDots can be used to visualize BMP-2 binding to BMPRIa.
- MβCD demonstrates potential in restoring BMPRIa function and BMP signaling, suggesting a promising therapeutic avenue for osteoporosis associated with aging.
