Author's response

Abstract

Thank you for your letter. I agree that this is an interesting subject, which can be crucial for the biology of orthodontic tooth movement (OTM). It has been well known for 100 years that aseptic inflammation regulates the biological process of bone resorption during OTM. There must exist a mechanism that controls inflammation and the resorptive process to prevent the pathogenesis induced by orthodontic loading. However, factors that subside the orthodontic inflammation to uphold homeostasis of the periodontal tissues are rarely studied. In our article, we suggested that autophagy may serve as such a regulatory role during OTM. In addition, the administration of an autophagy activator (eg, rapamycin) decreases tooth movement and osteoclast recruitment in rats, suggesting that autophagy could downregulate the inflammatory response during OTM.1Li Y. Jacox L.A. Coats S. Kwon J. Xue P. Tang N. et al.Roles of autophagy in orthodontic tooth movement.Am J Orthod Dentofacial Orthop. 2021; 159: 582-593Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Furthermore, Jacox et al2Jacox L. Tang N. Li Y. Bocklage C. Coats S. Graves C. et al.Orthodontic loading activates cell-specific autophagy in a force-dependent manner.Am J Orthod Dentofac Orthop. 2021; (In press)PubMed Google Scholar demonstrated that autophagy is primarily induced in macrophage-lineage cells (the precursor of osteoclast) by orthodontic loading in a force-dependent manner and plays a role during OTM. In the early 1990s, King et al3King G.J. Keeling S.D. Wronski T.J. Histomorphometric study of alveolar bone turnover in orthodontic tooth movement.Bone. 1991; 12: 401-409Crossref PubMed Scopus (135) Google Scholar showed hypoxia-inducible factor-1α (HIF-1α) was induced as early as 12 hours after the application of compressive force during OTM. Other studies have shown that HIF-1α could bind to hypoxia response elements of >100 genes (eg, VEGF and BNIP3) and regulates their production.4Bellot G. Garcia-Medina R. Gounon P. Chiche J. Roux D. Pouysségur J. et al.Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.Mol Cell Biol. 2009; 29: 2570-2581Crossref PubMed Scopus (978) Google Scholar More evidence supports crosstalk between HIF-1α and autophagy.5Quäschling T. Friedrich D. Deepe Jr., G.S. Rupp J. Crosstalk Between autophagy and hypoxia-inducible factor-1α in antifungal immunity.Cells. 2020; 9: 2150Crossref Scopus (6) Google Scholar, 6Chen D. Wu L. Liu L. Gong Q. Zheng J. Peng C. et al.Comparison of HIF1A-AS1 and HIF1A-AS2 in regulating HIF-1α and the osteogenic differentiation of PDLCs under hypoxia.Int J Mol Med. 2017; 40: 1529-1536Crossref PubMed Scopus (25) Google Scholar, 7Zhang H. Bosch-Marce M. Shimoda L.A. Tan Y.S. Baek J.H. Wesley J.B. et al.Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.J Biol Chem. 2008; 283: 10892-10903Abstract Full Text Full Text PDF PubMed Scopus (1200) Google Scholar Thus, the letter hypothesizes that HIF-1α might be the initiator of OTM and autophagy. The findings from Li et al1Li Y. Jacox L.A. Coats S. Kwon J. Xue P. Tang N. et al.Roles of autophagy in orthodontic tooth movement.Am J Orthod Dentofacial Orthop. 2021; 159: 582-593Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar showed an increase in BECN1 (a macroautophagy gene) expression 3 days after loading indirectly supports this hypothesis. Although this can be a reasonable hypothesis, it would require rigorous investigations to unveil their upstream and downstream relationships. Recently, the Ko laboratory (Li’s colleague) reported that another autophagy gene (eg, optineurin [OPTN]) binds Nrf2 to regulate intracellular reactive oxygen species and the survival of bone cells.8Xue P. Hu X. Chang E. Wang L. Chen M. Wu T.-H. et al.Deficiency of optineurin enhances osteoclast differentiation by attenuating NRF-2 mediated antioxidant response.Exp Mol Med. 2021; 53: 667-680Crossref PubMed Scopus (3) Google Scholar Because a major role of HIF-1α is to prevent excess mitochondrial reactive oxygen species production under hypoxic conditions, it is possible both HIF-1α and optineurin may express parallel without a regulatory relationship. It is suggested that the hypothesis should depict specific autophagy forms such as macroautophagy, microautophagy, or mitophagy, etc. Hypoxia-inducible factor-1α may be the first host response in orthodontic tooth movementAmerican Journal of Orthodontics and Dentofacial OrthopedicsVol. 160Issue 2PreviewAn article published in the May 2021 issue of the American Journal of Orthodontics and Dentofacial Orthopedics advocated how orthodontic loading leads to activation of autophagy during orthodontic tooth movement (OTM); however, little is known about how it is regulated.1 The article included original research findings and was appreciated greatly, but it could be supplemented with some important information on the role of the first host response taking place during OTM, that is, hypoxia, as identified by some of the authors in a recent review article. Full-Text PDF