Loading-induced bone formation is mediated by Wnt1 induction in osteoblast-lineage cells.

Mechanical loading on the skeleton stimulates bone formation. Although the exact mechanism underlying this process remains unknown, a growing body of evidence indicates that the Wnt signaling pathway is necessary for the skeletal response to loading. Recently, we showed that Wnts produced by osteoblast lineage cells mediate the osteo-anabolic response to tibial loading in adult mice. Here, we report that Wnt1 specifically plays a crucial role in mediating the mechano-adaptive response to loading. Independent of loading, short-term loss of Wnt1 in the Osx-lineage resulted in a decreased cortical bone area in the tibias of 5-month-old mice. In females, strain-matched loading enhanced periosteal bone formation in Wnt1F/F controls, but not in Wnt1F/F; OsxCreERT2 knockouts. In males, strain-matched loading increased periosteal bone formation in both control and knockout mice; however, the periosteal relative bone formation rate was 65% lower in Wnt1 knockouts versus controls. Together, these findings show that Wnt1 supports adult bone homeostasis and mediates the bone anabolic response to mechanical loading.

Osteoblast-Specific Wnt Secretion Is Required for Skeletal Homeostasis and Loading-Induced Bone Formation in Adult Mice.

Wnt signaling is critical to many aspects of skeletal regulation, but the importance of Wnt ligands in the bone anabolic response to mechanical loading is not well established. Recent transcriptome profiling studies by our laboratory and others show that mechanical loading potently induces genes encoding Wnt ligands, including Wnt1 and Wnt7b. Based on these findings, we hypothesized that mechanical loading stimulates adult bone formation by inducing Wnt ligand expression. To test this hypothesis, we inhibited Wnt ligand secretion in adult (5 months old) mice using a systemic (drug) and a bone-targeted (conditional gene knockout) approach, and subjected them to axial tibial loading to induce lamellar bone formation. Mice treated with the Wnt secretion inhibitor WNT974 exhibited a decrease in bone formation in non-loaded bones as well as a 54% decline in the periosteal bone formation response to tibial loading. Next, osteoblast-specific Wnt secretion was inhibited by dosing 5-month-old Osx-CreERT2; WlsF/F mice with tamoxifen. Within 1 to 2 weeks of Wls deletion, skeletal homeostasis was altered with decreased bone formation and increased resorption, and the anabolic response to loading was reduced 65% compared to control (WlsF/F ). Together, these findings show that Wnt ligand secretion is required for adult bone homeostasis, and furthermore establish a role for osteoblast-derived Wnts in mediating the bone anabolic response to tibial loading. © 2021 American Society for Bone and Mineral Research (ASBMR).

Student Response Initiatives: A Case Study of COVID-19 at Washington University.

The COVID-19 pandemic disrupted medical education worldwide, leading medical students to organize response initiatives. This paper summarizes the Washington University Medical Student COVID-19 Response (WUMS-CR) and shares lessons to guide future initiatives. We used a three-principle framework of community needs assessment, faculty mentorship, and partnership with pre-existing organizations to address needs in St. Louis, including contact tracing and childcare. In total, over 12,000 h were volunteered across 15+ projects. Overall, student response initiatives should use appropriate frameworks to guide projects and should capitalize on volunteer participation, speed and flexibility, and the diversity of student interests and skills for maximal impact.

Old Mice Have Less Transcriptional Activation But Similar Periosteal Cell Proliferation Compared to Young-Adult Mice in Response to in vivo Mechanical Loading.

Mechanical loading is a potent strategy to induce bone formation, but with aging, the bone formation response to the same mechanical stimulus diminishes. Our main objectives were to (i) discover the potential transcriptional differences and (ii) compare the periosteal cell proliferation between tibias of young-adult and old mice in response to strain-matched mechanical loading. First, to discover potential age-related transcriptional differences, we performed RNA sequencing (RNA-seq) to compare the loading responses between tibias of young-adult (5-month) and old (22-month) C57BL/6N female mice following 1, 3, or 5 days of axial loading (loaded versus non-loaded). Compared to young-adult mice, old mice had less transcriptional activation following loading at each time point, as measured by the number of differentially expressed genes (DEGs) and the fold-changes of the DEGs. Old mice engaged fewer pathways and gene ontology (GO) processes, showing less activation of processes related to proliferation and differentiation. In tibias of young-adult mice, we observed prominent Wnt signaling, extracellular matrix (ECM), and neuronal responses, which were diminished with aging. Additionally, we identified several targets that may be effective in restoring the mechanoresponsiveness of aged bone, including nerve growth factor (NGF), Notum, prostaglandin signaling, Nell-1, and the AP-1 family. Second, to directly test the extent to which periosteal cell proliferation was diminished in old mice, we used bromodeoxyuridine (BrdU) in a separate cohort of mice to label cells that divided during the 5-day loading interval. Young-adult and old mice had an average of 15.5 and 16.7 BrdU+ surface cells/mm, respectively, suggesting that impaired proliferation in the first 5 days of loading does not explain the diminished bone formation response with aging. We conclude that old mice have diminished transcriptional activation following mechanical loading, but periosteal proliferation in the first 5 days of loading does not differ between tibias of young-adult and old mice. © 2020 American Society for Bone and Mineral Research.

Accessible Communication Tools for Surgical Site Infection Monitoring and Prevention in Joint Reconstruction: Feasibility Study.

BACKGROUND: The National Surgical Quality Improvement Program logs surgical site infections (SSIs) as the most common cause of unplanned postoperative readmission for a variety of surgical interventions. Hospitals are making significant efforts preoperatively and postoperatively to reduce SSIs and improve care. Telemedicine, defined as using remote technology to implement health care, has the potential to improve outcomes across a wide range of parameters, including reducing SSIs. OBJECTIVE: The purpose of this study was to assess the feasibility and user satisfaction of two automated messaging systems, EpxDecolonization and EpxWound, to improve perioperative care in a quality improvement project for patients undergoing total joint replacement. METHODS: We designed two automated text messaging and calling systems named EpxDecolonization, which reminded patients of their preoperative decolonization protocol, and EpxWound, which monitored pain, wound, and fever status postoperatively. Daily patient responses were recorded and a post-usage survey was sent out to participants to assess satisfaction with the systems. RESULTS: Over the 40-week study period, 638 and 642 patients were enrolled in EpxDecolonization (a preoperative decolonization reminder) and EpxWound (a postoperative surgical site infection telemonitoring system), respectively. Patients could be enrolled in either or both EpxDecolonization and EpxWound, with the default option being dual enrollment. The proportion of sessions responded to was 85.2% for EpxDecolonization and 78.4% for EpxWound. Of the 1280 patients prescribed EpxWound and EpxDecolonization, 821 (64.14%) fully completed the postoperative system satisfaction survey. The median survey score (scale 1-9) was 9 for patient-rated overall care and 8 for whether the telemonitoring systems improved patient communication with providers. The majority of patients (69.0%, 566/821) indicated that the systems sent out an ideal number of messages (not too many, not too few). CONCLUSIONS: EpxDecolonization and EpxWound demonstrated high response rates and improved patient-rated communication with providers. These preliminary data suggest that these systems are well tolerated and potentially beneficial to both patients and providers. The systems have the potential to improve both patient satisfaction scores and compliance with preoperative protocols and postoperative wound monitoring. Future efforts will focus on testing the sensitivity and specificity of alerts generated by each system and on demonstrating the ability of these systems to improve clinical quality metrics with more authoritative data.

Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation.

Maximal exercise-associated oxidative capacity is strongly correlated with health and longevity in humans. Rats selectively bred for high running capacity (HCR) have improved metabolic health and are longer-lived than their low-capacity counterparts (LCR). Using metabolomic and proteomic profiling, we show that HCR efficiently oxidize fatty acids (FAs) and branched-chain amino acids (BCAAs), sparing glycogen and reducing accumulation of short- and medium-chain acylcarnitines. HCR mitochondria have reduced acetylation of mitochondrial proteins within oxidative pathways at rest, and there is rapid protein deacetylation with exercise, which is greater in HCR than LCR. Fluxomic analysis of valine degradation with exercise demonstrates a functional role of differential protein acetylation in HCR and LCR. Our data suggest that efficient FA and BCAA utilization contribute to high intrinsic exercise capacity and the health and longevity benefits associated with enhanced fitness.