FAK Promotes Early Osteoprogenitor Cell Proliferation by Enhancing mTORC1 Signaling

Focal adhesion kinase (FAK) has important functions in bone homeostasis but its role in early osteoprogenitor cells is unknown. We show herein that mice lacking FAK in Dermo1- expressing cells exhibited low bone mass and decreased osteoblast number. Mechanistically, FAK- deficient early osteoprogenitor cells had decreased proliferation and significantly reduced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, a central regulator of cell growth and proliferation. Furthermore, our data showed that the pharmacological inhibition of FAK kinase- dependent function alone was sufficient to decrease the proliferation and compromise the mineralization of early osteoprogenitor cells. In contrast to the Fak deletion in early osteoprogenitor cells, FAK loss in Col3.6 Cre- targeted osteoblasts did not cause bone loss, and Fak deletion in osteoblasts did not affect proliferation, differentiation, and mTORC1 signaling but increased the level of active proline- rich tyrosine kinase 2 (PYK2), which belongs to the same non- receptor tyrosine kinase family as FAK. Importantly, mTORC1 signaling in bone marrow stromal cells (BMSCs) was reduced if FAK kinase was inhibited at the early osteogenic differentiation stage. In contrast, mTORC1 signaling in BMSCs was not affected if FAK kinase was inhibited at a later osteogenic differentiation stage, in which, however, the concomitant inhibition of both FAK kinase and PYK2 kinase reduced mTORC1 signaling. In summary, our data suggest that FAK promotes early osteoprogenitor cell proliferation by enhancing mTORC1 signaling via its kinase- dependent function and the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2. © 2020 American Society for Bone and Mineral Research.Schematic model of the differential roles of FAK in the cells of osteoblast lineage. The model depicts the mechanisms of FAK action at three distinct stages of osteoblast lineage in which the roles of FAK have been addressed by genetic and pharmacological approaches as well as the respective Cre transgenes used to target Fak, including Dermo1- Cre (this study), Osterix- Cre,(10) Col3.6- Cre (this study), and Col2.3- Cre.(9) Red - indicates that the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/3/jbmr4029-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/2/jbmr4029_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/1/jbmr4029.pd

Cardiovascular Response of Aged Outpatients With Systemic Diseases During Tooth Extraction: A Single-Center Retrospective Observational Study

BackgroundAged people are maintaining many natural teeth due to improved oral health. However, compromised general health and poor oral hygiene habits at earlier ages resulted in poor status of preserved teeth. Therefore, tooth extraction is required in many aged people. More knowledge is needed because there are many risk factors during the surgery in frail aged adults. The aim of this study was to evaluate the cardiovascular response of such a population during tooth extraction and analyze risk factors to provide clinical guidance.MethodsA retrospective study was performed on aged patients with systemic diseases who underwent tooth extraction. Data regarding demographic profiles and cardiovascular parameters of heart rate and blood pressure were collected preoperative, when local anesthesia was administered, at the beginning of tooth extraction, 5 min after tooth extraction, and postoperative. The effects of risk factors, including age, sex, and systemic diseases on these parameters were analyzed with a multilevel model.ResultsHeart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) of aged patients increased significantly when performing local anesthesia and tooth extraction. During the operation, the older patients (β = 2.011, P = 0.005) and the diabetics (β = 3.902, P < 0.0001) were associated with higher SBP, while those with more tooth extractions exhibited higher HR (β = 0.893, P = 0.007). Women patients showed both significantly elevated HR (β = 1.687, P < 0.0001) and SBP (β = 2.268, P < 0.0001). However, for coronary artery disease patients, HR (β = −2.747, P < 0.0001) and blood pressure [SBP (β = −4.094, P < 0.0001) and DBP (β = −0.87, P = 0.016)] were markedly lower than those of patients without a diagnosis of coronary artery disease.ConclusionCardiovascular response of aged outpatients with systemic diseases during tooth extraction is quite significant. Age, sex, systemic diseases, and the number of tooth extraction could be risk factors closely associated with cardiovascular response. The findings might provide safety guidance for dentists on tooth extraction in this population

Synchronous multimode ultrasound for assessing right-to-left shunt: a prospective clinical study

BackgroundRight-to-left shunt (RLS) is associated with several conditions and causes morbidity. In this study, we aimed to evaluate the effectiveness of synchronous multimode ultrasonography in detecting RLS.MethodsWe prospectively enrolled 423 patients with high clinical suspicion of RLS and divided them into the contrast transcranial Doppler (cTCD) group and synchronous multimode ultrasound group, in which both cTCD and contrast transthoracic echocardiography (cTTE) were performed during the same process of contrast-enhanced ultrasound imaging. The simultaneous test results were compared with those of cTCD alone.ResultsThe positive rates of grade II (22.0%:10.0%) and III (12.7%:10.8%) shunts and the total positive rate (82.1748%) in the synchronous multimode ultrasound group were higher than those in the cTCD alone group. Among patients with RLS grade I in the synchronous multimode ultrasound group, 23 had RLS grade I in cTCD but grade 0 in synchronous cTTE, whereas four had grade I in cTCD but grade 0 in synchronous cTTE. Among patients with RLS grade II in the synchronous multimode ultrasound group, 28 had RLS grade I in cTCD but grade II in synchronous cTTE. Among patients with RLS grade III in the synchronous multimode ultrasound group, four had RLS grade I in cTCD but grade III in synchronous cTTE. Synchronous multimode ultrasound had a sensitivity of 87.5% and specificity of 60.6% in the patent foramen ovale (PFO) diagnosis. Binary logistic regression analyses showed that age (odds ratio [OR] = 1.041) and risk of paradoxical embolism score ≥ 7 (OR = 7.798) were risk factors for stroke recurrence, whereas antiplatelets (OR = 0.590) and PFO closure with antiplatelets (OR = 0.109) were protective factors.ConclusionSynchronous multimodal ultrasound significantly improves the detection rate and test efficiency, quantifies RLS more accurately, and reduces testing risks and medical costs. We conclude that synchronous multimodal ultrasound has significant potential for clinical applications

Clinical analysis of medication related osteonecrosis of the jaws: A growing severe complication in China

Background/purpose: Medication-related osteonecrosis of the jaws (MRONJ) is an unusual but quite serious complication. However, its mechanism remains unclear, and its treatment protocol is still controversial. Materials and methods: Our study involved 201 osteonecrosis of the jaw (ONJ) patients from September 2006 to March 2017. We analyzed risk factors, clinical characteristics, treatment, etc., by comparing MRONJ with other ONJs. Results: Among 201 patients, MRONJ accounted for 14.71% and it presented a consistent increase tendency. In comparison with other ONJs, we considered advanced age, maxilla lesion, diabetes mellitus, tooth extraction, especially multi-teeth extraction as risk factors (P  0.05). 81.3% patients with advanced stage showed complete or partial healing lesions after surgery. Conclusion: Advanced age, maxilla lesion, diabetes mellitus, tooth extraction seem to be important triggering factors for MRONJ. Clinicians and surgeons should pay attention to maxillary lesions as it is related to severe symptoms and unfavorable prognosis. Once diagnosed as MRONJ, surgery is an effective treatment for patients with advanced stage. Keywords: Bisphosphate, Osteonecrosis, Risk factor, Treatmen

Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells

Abstract Pulmonary arterial hypertension (PAH) is a pathophysiological state of abnormally elevated pulmonary arterial pressure caused by drugs, inflammation, toxins, viruses, hypoxia, and other risk factors. We studied the therapeutic effect and target of tetramethylpyrazine (tetramethylpyrazine [TMP]; ligustrazine) in the treatment of PAH and we speculated that dramatic changes in myocardin levels can significantly affect the progression of PAH. In vivo, the results showed that administration of TMP significantly prolonged the survival of PAH rats by reducing the proliferative lesions, right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and the Fulton index in the heart and lung of PAH rats. In vitro, TMP can regulate the levels of smooth muscle protein 22‐alpha (SM22‐α), and myocardin as well as intracellular cytokines such as NO, transforming growth factor beta (TGF‐β), and connective tissue growth factor (CTGF) in a dose‐dependent manner (25, 50, or 100 μM). Transfection of myocardin small interfering RNA (siRNA) aggravated the proliferation of pulmonary artery smooth muscle cells (PSMCs), and the regulatory effect of TMP on α‐smooth muscle actin (α‐SMA) and osteopontin (OPN) disappeared. The application of 10 nM estrogen receptor alpha (ERα) inhibitor MPP promoted the proliferation of PSMCs, but it does not affect the inhibition of TMP on PSMCs proliferation. Finally, we found that TMP promoted the nucleation of myocardin‐related transcription factor‐A (MRTF‐A) and combined it with myocardin. In conclusion, TMP can inhibit the transformation of PSMCs from the contractile phenotype to the proliferative phenotype by promoting the formation of the nuclear (MRTF‐A/myocardin) transcription complex to treat PAH