skeletal-phenotype-analysis-conditional-stat3-deletion-mouse

Skeletal Phenotype Analysis of a Conditional <em>Stat3</em> Deletion Mouse Model

Transgenic mouse models are powerful for understanding the critical genes controlling osteoclast differentiation and activity, and for studying mechanisms ...

National Clinical Research Center of Stomatology

The aim of the study was to study the specific morphological features of alveolar bone and compare it to femoral bone in rats.

The Specific Morphological Features of Alveolar Bone.

Orthodontic treatment is more complicated when both soft and hard tissues must be considered because an impacted maxillary canine has important effects on function and esthetics. Compared with extraction of impacted maxillary canines, exposure followed by orthodontic traction can improve esthetics and better protect the patient's teeth and alveolar bone. Therefore, in order to achieve desirable tooth movement with minimal unexpected complications, a precise diagnosis is indispensable to establish an effective and efficient force system. In this report, we describe the case of a 31-year-old patient who had a labio-palatal horizontally impacted maxillary left canine with a severe occlusal alveolar bone defect and a missing maxillary left first premolar. Herein, with the aid of three-dimensional imaging, sequential traction was performed with a three-directional force device that finally achieved acceptable occlusion by bringing the horizontally impacted maxillary left canine into alignment. The maxillary left canine had normal gingival contours and was surrounded by a substantial amount of regenerated alveolar bone. The 1-year follow-up stability assessment demonstrated that the esthetic and functional outcomes were successful.

Sequential traction of a labio-palatal horizontally impacted maxillary canine with a custom three-directional force device in the space of a missing ipsilateral first premolar.

The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a central role in cell survival and function. STAT3 has been demonstrated to participate in the maintenance of bone homeostasis in osteoblasts, but its role in osteoclasts  remains poorly defined. Here, we generated a conditional knockout mouse model in which  was deleted in osteoclasts using a cathepsin K-Cre (Ctsk-Cre) driver. We observed that osteoclast-specific  deficiency caused increased bone mass in mice, which we attributed to impaired bone catabolism by osteoclasts. -deficient bone marrow macrophages (BMMs) showed decreased expression of nuclear factor of activated T cells, cytoplasm 1 (NFATc1), and reduced osteoclast differentiation determined by decreases in osteoclast number, tartrate-resistant acid phosphatase activity, and expression of osteoclast marker genes. Enforced expression of NFATc1 in -deficient BMMs rescued the impaired osteoclast differentiation. Mechanistically, we revealed that STAT3 could drive the transcription of NFATc1 by binding to its promoter. Furthermore, preventing STAT3 activation by using an inhibitor of upstream phosphorylases, AG490, also impaired osteoclast differentiation and formation in a similar way as gene deletion of  In summary, our data provide the first evidence that STAT3 is significant in osteoclast differentiation and bone homeostasis , and it may be identified as a potential pharmacological target for the treatment of bone metabolic diseases through regulation of osteoclast activity.

STAT3 controls osteoclast differentiation and bone homeostasis by regulating NFATc1 transcription.

Alveolar bone osteoporosis has attracted more and more attention because of its profound impact on stomatognathic function and treatment, but current treatments have not been targeted to alveolar bone and might even cause severe side effects. Thus, identifying the effects of anti-osteoporosis agents on alveolar bone is essential. Icariin ameliorates metabolic dysfunction of long bones, but its effects on alveolar bone remain unclarified.

Icariin prevents oestrogen deficiency-induced alveolar bone loss through promoting osteogenesis via STAT3.

Based on the Cre-Loxp gene knockout system, this study intended to construct tamoxifen-inducible STAT3 conditional knockout mice and verify the knockout efficiency.

[Generation and validation of inducible osteoblast-specific Stat3 knockout mice].

Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5(Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments.

STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis.

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).

Article	Year
The Specific Morphological Features of Alveolar Bone. The Journal of craniofacial surgery\| PubMed ID: 29498973	2018
Sequential traction of a labio-palatal horizontally impacted maxillary canine with a custom three-directional force device in the space of a missing ipsilateral first premolar. Korean journal of orthodontics\| PubMed ID: 30941299	2019
STAT3 controls osteoclast differentiation and bone homeostasis by regulating NFATc1 transcription. The Journal of biological chemistry\| PubMed ID: 31462535	2019
Icariin prevents oestrogen deficiency-induced alveolar bone loss through promoting osteogenesis via STAT3. Cell proliferation\| PubMed ID: 31943455	2020
[Generation and validation of inducible osteoblast-specific Stat3 knockout mice]. Shanghai kou qiang yi xue = Shanghai journal of stomatology\| PubMed ID: 33089278	2020
STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis. Nature communications\| PubMed ID: 34824272	2021
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

Xinyi Gong

Biography

JoVE Journal Publications

Other Publications