Higenamine Promotes Osteogenesis Via IQGAP1/SMAD4 Signaling Pathway and Prevents Age- and Estrogen-Dependent Bone Loss in Mice.

Osteoporosis is a common bone disease caused by an imbalance of bone resorption and formation that results in a loss of total bone density. SMAD2/3 signal transduction is known to play a crucial role in osteogenic differentiation through transforming growth factor-beta (TGF-ß). By screening a library of small-molecule compounds, the current study identifies higenamine (HG) as an active osteogenic agent that could be a therapeutic candidate for osteoporosis. In vitro data demonstrated that HG effectively induced expressions of osteogenic markers in mouse bone marrow stromal cell (BMSCs) and preosteoblastic cell cultures. Further, HG treatment resulted in enhanced bone formation and prevented accelerated bone loss on two animal models that mimic spontaneous senile osteoporosis and postmenopausal osteoporosis. IQ motif-containing GTPase-activating protein 1 (IQGAP1) was confirmed as a novel target of HG, where HG appears to bind to the Glu-1019 site of IQGAP1 to exert its osteogenic effects. Data subsequently suggested that HG promoted phosphorylation of SMAD2/3 and regulated the SMAD2/3 pathway by inhibiting SMAD4 ubiquitination. Overall, the findings highlight HG as a new small-molecule drug to promote bone formation through SMAD2/3 pathway in osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).

DEPDC1 as a crucial factor in the progression of human osteosarcoma.

OBJECTIVE: Novel therapeutic strategies are emerging with the increased understanding of the underlying mechanisms of human osteosarcoma. This current study tends to decipher the potentially critical role of DEP domain-containing 1 (DEPDC1), a tumor-related gene, during the progression of osteosarcoma. METHODS: Bioinformatics analysis of 25,035 genes from the National Center for Biotechnology Information (NCBI) databases was performed to screen differentially expressed genes between osteosarcoma and normal control groups, complemented by the examination of 85 clinical osteosarcoma specimens. Furthermore, the manipulation of DEPDC1 expression levels by using silencing RNA (siRNA) or lentiviral vector intervention on human osteosarcoma cells was performed to reveal its role and interactions in in vitro and in vivo settings. RESULTS: Gene expression profile analysis and immunohistochemical (IHC) examination suggested that DEPDC1 is highly expressed in human osteosarcoma cells and tumor tissue. The silencing of DEPDC1 arrested osteosarcoma cell proliferation, promoted apoptosis, and ceased tumor metastasis. Studies involving clinical human osteosarcoma cases exhibited a strong correlation of DEPDC1 over-expressed osteosarcoma specimens with a reduced patient survival rate. CONCLUSIONS: Collectively, this study demonstrated that DEPDC1 is a critical driver in the promotion of osteosarcoma progression and results in poor patient prognosis. Genetically targeting or pharmacologically inhibiting DEPDC1 may serve as a promising strategy for treating human osteosarcoma.

Human Peripheral Nerve-Derived Pluripotent Cells Can Be Stimulated by In Vitro Bone Morphogenetic Protein-2.

We have recently identified a population of cells within the peripheral nerves of adult rodent animals (mice and rats) that can respond to Bone Morphogenetic Protein-2 (BMP-2) exposure or physical injury to rapidly proliferate. More importantly, these cells exhibited embryonic differentiation potentials that could be induced into osteoblastic and endothelial cells in vitro. The current study examined human nerve specimens to compare and characterize the cells after BMP-2 stimulation. Fresh pieces of human nerve tissue were minced and treated with either BMP-2 (750 ng/mL) or a PBS vehicle for 12 h at 37 °C, before being digested in 0.2% collagenase and 0.05% trypsin-EDTA. Isolated cells were cultured in a restrictive stem cell medium. Significantly more cells were obtained from the nerve pieces with the BMP-2 treatment in comparison with the PBS vehicle controls. Cell colonies started to form at Day 3. Expressions of the four transcription factors, namely, Klf4, c-Myc, Sox2, and Oct4, were confirmed at both the transcriptional and translational levels. The cells can be maintained in the stem cell culture medium for at least 6 weeks without changing their morphology. When the cells were transferred to a fibroblast growth medium, dispersed spindle-shaped motile cells were noted and became fibroblast activated protein-α (FAP) positive with immunocytochemistry staining. The data suggest that human peripheral nerve tissue also contains a population of cells that can respond to BMP-2 and express Klf4, Sox2, cMyc, and Oct4-the four transcription factors driving cell pluripotency. These cells are able to differentiate into FAP-positive fibroblasts. In summary, in human peripheral nerves also reside a population of quiescent cells with pluripotency potential that may be the same cells as rodent nerve-derived adult stem (NEDAPS) cells. It is proposed that these cells are possibly at the core of a previously unknown natural mechanism for healing an injury.

Work engagement, job satisfaction, and turnover intentions among family medicine residency program managers.

OBJECTIVES: The authors examined the associations between work engagement, job satisfaction, and turnover intentions among family medicine residency (FMR) managers. METHODS: We conducted a cross-sectional online survey of 511 FMR manager members of the Association of Family Medicine Administration using purposive sampling. The Utrecht Work Engagement Scale, Job Satisfaction Survey, and Boshoff and Allen's 3-item scale were used to assess work engagement, job satisfaction, and turnover intentions respectively. Descriptive statistics, Chi-Square tests, Pearson's correlations, 2-way contingency table analysis, and hierarchical regression analyses were used to analyze the data. RESULTS: The response rate was 70.6% (389/551). Work engagement was positively correlated with job satisfaction (r[387]=.513, p<.001) and negatively correlated with turnover intentions (r[368]=.580, p<.001). Turnover intention was negatively correlated with job satisfaction (r[387]=-.690, p<.001). Positive assessment of nature of work (t[364]=15.06, p<.001), fringe benefits (t[364]=6.89, p<.001), communication (t[364]=2.27, p<.05), and promotion (t[364]=2.48, p<.05) predicted work engagement. Work engagement (t[364]=-4.31, p<.001), pay (t[364]=-3.71, p<.001), supervision (t[364]=-3.51, P<.01), contingent rewards (t[364]=-2.39, p<.05), nature of work (t[364]=-2.16, p<.05), and communication (t[364]=-2.15, p<.05) predicted turnover intentions. CONCLUSIONS: Our findings demonstrate associations between work engagement, job satisfaction, and turnover intentions. When medical residency managers are emotionally and cognitively engaged at work, they tend to remain in the organization, validating and rewarding organizations that foster employee engagement. Further studies are needed to establish a causal relationship between work engagement, job satisfaction, and turnover intentions and to investigate other potential factors that could contribute to enriching the job satisfaction of this crucial group of professionals.