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Using Inducible Osteoblastic Lineage-Specific <em>Stat3</em> Knockout Mice to Study Alveolar Bone Remodeling During Orthodontic Tooth Movement

The alveolar bone, with a high turnover rate, is the most actively-remodeling bone in the body. Orthodontic tooth movement (OTM) is a common artificial ...

Shanghai Jiao Tong University School of Medicine

Shanghai Jiao Tong University

National Center for Stomatology

National Clinical Research Center for Oral Diseases

Shanghai Key Laboratory of Stomatology

Mechanical force is essential to shape the internal architecture and external form of the skeleton by regulating the bone remodeling process. However, the underlying mechanism of how the bone responds to mechanical force remains elusive. Here, we generated both orthodontic tooth movement (OTM) model in vivo and a cyclic stretch-loading model in vitro to investigate biomechanical regulation of the alveolar bone. In this study, signal transducer and activator of transcription 3 (STAT3) was screened as one of the mechanosensitive proteins by protein array analysis of cyclic stretch-loaded bone mesenchymal stem cells (BMSCs) and was also proven to be activated in osteoblasts in response to the mechanical force during OTM. With an inducible osteoblast linage-specific Stat3 knockout model, we found that Stat3 deletion decelerated the OTM rate and reduced orthodontic force-induced bone remodeling, as indicated by both decreased bone resorption and formation. Both genetic deletion and pharmacological inhibition of STAT3 in BMSCs directly inhibited mechanical force-induced osteoblast differentiation and impaired osteoclast formation via osteoblast-osteoclast cross-talk under mechanical force loading. According to RNA-seq analysis of Stat3-deleted BMSCs under mechanical force, matrix metalloproteinase 3 (Mmp3) was screened and predicted to be a downstream target of STAT3. The luciferase and ChIP assays identified that Stat3 could bind to the Mmp3 promotor and upregulate its transcription activity. Furthermore, STAT3-inhibitor decelerated tooth movement through inhibition of the bone resorption activity, as well as MMP3 expression. In summary, our study identified the mechanosensitive characteristics of STAT3 in osteoblasts and highlighted its critical role in force-induced bone remodeling during orthodontic tooth movement via osteoblast-osteoclast cross-talk. © 2022 American Society for Bone and Mineral Research (ASBMR).

Osteoblastic STAT3 Is Crucial for Orthodontic Force Driving Alveolar Bone Remodeling and Tooth Movement.

Bone exhibits changes in density, strength, and microarchitecture in relation to mechanical loading mediated by exercise. Appropriate exercise maintains bone homeostasis, while the absence of exercise leads to disuse bone loss. However, the acting mechanism of mechanotransduction in bone remains unclear. We performed the running-wheel exercise and tail suspension model to study the effects of exercise on bone metabolism, and found that osteoblastic Signal transducer and activator of transcription 3 (STAT3) activity was closely related to exercise-induced bone mass and metabolism changes. With the Flexcell tension-loading system , mechanical force promoted STAT3 activity, which was accompanied by increased osteoblastic differentiation of the bone marrow mesenchymal stem cells (BMSCs). In contrast, the inhibition of STAT3 phosphorylation blocked force-induced osteoblastic differentiation. Furthermore, pharmacological inactivation of STAT3 impaired the increase in exercise-induced bone mass and osteogenesis. With an inducible conditional deletion mouse model, we found that the osteoblast lineage-specific Stat3 deletion could also block force-induced osteoblastic differentiation  and impair exercise-promoted bone mass and osteogenesis . This confirmed the crucial role of osteoblastic STAT3 in exercise-mediated bone metabolism. Finally, colivelin, a STAT3 agonist, promoted osteoblastic differentiation  and partly rescued exercise loss-induced disuse bone loss by improving osteogenesis in the tail suspension model. Taken together, our study revealed the essential role of STAT3 in maintaining exercise-mediated bone homeostasis. In addition, STAT3 might act as a potential target for osteoporosis caused by exercise loss.

Exercise maintains bone homeostasis by promoting osteogenesis through STAT3.

Periodontal ligament (PDL) and dental pulp (DP) share a common origin but have distinct biological and mechanical functions. To what extent the mechanoresponsive property of PDL can be attributed to its unique transcriptional profiles of cellular heterogeneity is unclear. This study aims to decipher cellular heterogeneity and distinct mechanoresponsive characteristics of odontogenic soft tissues and their underlying molecular mechanisms.

Article	Year
Osteoblastic STAT3 Is Crucial for Orthodontic Force Driving Alveolar Bone Remodeling and Tooth Movement. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research\| PubMed ID: 36370067	2023
Exercise maintains bone homeostasis by promoting osteogenesis through STAT3. International journal of biological sciences\| PubMed ID: 37151888	2023
ScRNA-seq links dental fibroblasts heterogeneity with mechanoresponsiveness. Journal of periodontal research\| PubMed ID: 37221903	2023

Yuanqi Liu

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