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Journal article
The TrkA agonist gambogic amide augments skeletal adaptation to mechanical loading
Bone (New York, N.Y.), v 147, 115908
01 Jun 2021
PMID: 33713848
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The periosteal and endosteal surfaces of mature bone are densely innervated by sensory nerves expressing TrkA, the high-affinity receptor for nerve growth factor (NGF). In previous work, we demonstrated that administration of exogenous NGF significantly increased load-induced bone formation through the activation of Wnt signaling. However, the translational potential of NGF is limited by the induction of substantial mechanical and thermal hyperalgesia in mice and humans. Here, we tested the effect of gambogic amide (GA), a recently identified robust small molecule agonist for TrkA, on hyperalgesia and load-induced bone formation. Behavioral analysis was used to assess pain up to one week after axial forelimb compression. Contrary to our expectations, GA treatment was not associated with diminished use of the loaded forelimb or sensitivity to thermal stimulus. Furthermore, dynamic histomorphometry revealed a significant increase in relative periosteal bone formation rate as compared to vehicle treatment. Additionally, we found that GA treatment was associated with an increase in the number of osteoblasts per bone surface in loaded limbs as well as a significant increase in the fold change of Ngf, Wnt7b, and Axin2 mRNA expression as compared to vehicle (control). To test the effect of GA on osteoblasts directly, we cultured MC3T3-E1 cells for up to 21 days in osteogenic differentiation media containing NGF, GA, or vehicle (control). Media containing GA induced the significant upregulation of the osteoblastic differentiation markers Runx2, Bglap2, and Sp7 in a dose-dependent manner, whereas treatment with NGF was not associated with any significant increases in these markers. Furthermore, consistent with our in vivo findings, we observed that administration of 50 nM of GA upregulated expression of Ngf at both Day 3 and Day 7. However, cells treated with the highest dose of GA (500 nM) had significantly increased apoptosis and impaired cell proliferation. In conclusion, our study indicates GA may be useful for augmenting skeletal adaptation to mechanical forces without inducing hyperalgesia.
• Gambogic amide increased load-induced bone formation in mice.
• In contrast to NGF, gambogic amide is not associated with increased sensitivity to mechanical or thermal stimuli.
• Gambogic amide is able to affect osteoblasts that do not express TrkA.
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Details
- Title
- The TrkA agonist gambogic amide augments skeletal adaptation to mechanical loading
- Creators
- Gabriella Fioravanti - Thomas Jefferson UniversityPhuong Q. Hua - Drexel UniversityRyan E. Tomlinson - Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, United States of America
- Publication Details
- Bone (New York, N.Y.), v 147, 115908
- Publisher
- Elsevier Inc
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000643707100015
- Scopus ID
- 2-s2.0-85102638307
- Other Identifier
- 991021860654204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Endocrinology & Metabolism