We have previously identified osteoactivin (OA), encoded by Gpnmb, as an osteogenic factor that stimulates osteoblast differentiation in vitro. To elucidate the importance of OA in osteogenesis, we characterized the skeletal phenotype of a mouse model, DBA/2J (D2J) with a loss-of-function mutation in Gpnmb. Microtomography of D2J mice showed decreased trabecular mass, compared to that in wild-type mice [DBA/2J-Gpnmb(+)/SjJ (D2J/Gpnmb(+))]. Serum analysis showed decreases in OA and the bone-formation markers alkaline phosphatase and osteocalcin in D2J mice. Although D2J mice showed decreased osteoid and mineralization surfaces, their osteoblasts were increased in number, compared to D2J/Gpnmb(+) mice. We then examined the ability of D2J osteoblasts to differentiate in culture, where their differentiation and function were decreased, as evidenced by low alkaline phosphatase activity and matrix mineralization. Quantitative RT-PCR analyses confirmed the decreased expression of differentiation markers in D2J osteoblasts. In vitro, D2J osteoblasts proliferated and survived significantly less, compared to D2J/Gpnmb(+) osteoblasts. Next, we investigated whether mutant OA protein induces endoplasmic reticulum stress in D2J osteoblasts. Neither endoplasmic reticulum stress markers nor endoplasmic reticulum ultrastructure were altered in D2J osteoblasts. Finally, we assessed underlying mechanisms that might alter proliferation of D2J osteoblasts. Interestingly, TGF-β receptors and Smad-2/3 phosphorylation were up-regulated in D2J osteoblasts, suggesting that OA contributes to TGF-β signaling. These data confirm the anabolic role of OA in postnatal bone formation.

Osteoactivin (OA) is a novel osteogenic factor important for osteoblast differentiation and function. Previous studies showed that OA stimulates matrix mineralization and transcription of osteoblast specific genes required for differentiation. OA plays a role in wound healing and its expression was shown to increase in post fracture calluses. OA expression was reported in muscle as OA is upregulated in cases of denervation and unloading stress. The regulatory mechanisms of OA in muscle and bone have not yet been determined. In this study, we examined whether OA plays a role in transdifferentiation of C2C12 myoblast into osteoblasts. Infected C2C12 with a retroviral vector overexpressing OA under the CMV promoter were able to transdifferentiate from myoblasts into osteoblasts. Immunofluorescence analysis showed that skeletal muscle marker MF-20 was severely downregulated in cells overexpressing OA and contained significantly less myotubes compared to uninfected control. C2C12 myoblasts overexpressing OA showed an increase in expression of bone specific markers such as alkaline phosphatase and alizarin red staining, and also showed an increase in Runx2 protein expression. We also detected increased levels of phosphorylated focal adhesion kinase (FAK) in C2C12 myoblasts overexpressing OA compared to control. Taken together, our results suggest that OA is able to induce transdifferentiation of myoblasts into osteoblasts through increasing levels of phosphorylated FAK.

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INTRODUCTION: Resident involvement in surgical procedures is a critical component of resident education. As learners train, it is important to recognize the impact this has on patient outcomes. This project aims to describe the association between resident involvement in vaginal hysterectomies and patient outcomes. METHODS: The National Surgical Quality Improvement Project database was used to collect data on patients who underwent a vaginal hysterectomy from 2007 and 2012. Patients with incomplete data were excluded. Logistic and linear regression models were used for analysis. Significance was set at P=.05. RESULTS: A total of 7,838 patients were included. Of those, 38.6% of procedures included a resident and 61.4% were performed by an attending alone. Resident participation was associated with an increase in operative by 36.5 minutes, on average (P<.001, 95% CI 34.1-39.0). Resident involvement had no effect on post-operative length of stay (P=.953, OR 0.003, 95% CI -0.79-0.84), superficial surgical site infection (SSI) (P=.395, OR 1.285, 95% CI 0.722-2.287), organ space SSI (P=.135, OR 1.425, 95% CI 0.895-2.269), wound dehiscence (P=.182, OR 3.178, 95% CI 0.582-15.362), bleeding complications requiring transfusion (P=.540, OR 1.135, 95% CI 0.755-1.709), peripheral nerve injury (P=.342, OR 2.383, 95% CI 0.398-14.269), reoperation (P=.937, OR 1.042, 95% CI 0.376-2.890), or readmission (P=.725, OR 1.128, 95% CI 0.576-2.207). CONCLUSION: Inclusion of residents in surgical cases was not associated with any differences in complications measured with only a minor increase in operative time. This demonstrates the minimal impact of resident education on clinical outcomes, further arguing the need to include residents in cases whenever possible.

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