Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

Interrelationships between Cellular Density,Mosaic Patterning,and Dendritic Coverage of VGluT3 Amacrine Cells

Amacrine cells of the retina are conspicuously variable in their morphologies, their population demographics, and their ensuing functions. Vesicular glutamate transporter 3 (VGluT3) amacrine cells are a recently characterized type of amacrine cell exhibiting local dendritic autonomy. The present analysis has examined three features of this VGluT3 population, including their density, local distribution, and dendritic spread, to discern the extent to which these are interrelated, using male and female mice. We first demonstrate that Bax-mediated cell death transforms the mosaic of VGluT3 cells from a random distribution into a regular mosaic. We subsequently examine the relationship between cell density and mosaic regularity across recombinant inbred strains of mice, finding that, although both traits vary across the strains, they exhibit minimal covariation. Other genetic determinants must therefore contribute independently to final cell number and to mosaic order. Using a conditional KO approach, we further demonstrate that Bax acts via the bipolar cell population, rather than cell-intrinsically, to control VGluT3 cell number. Finally, we consider the relationship between the dendritic arbors of single VGluT3 cells and the distribution of their homotypic neighbors. Dendritic field area was found to be independent of Voronoi domain area, while dendritic coverage of single cells was not conserved, simply increasing with the size of the dendritic field. Bax-KO retinas exhibited a threefold increase in dendritic coverage. Each cell, however, contributed less dendrites at each depth within the plexus, intermingling their processes with those of neighboring cells to approximate a constant volumetric density, yielding a uniformity in process coverage across the population.SIGNIFICANCE STATEMENT Different types of retinal neuron spread their processes across the surface of the retina to achieve a degree of dendritic coverage that is characteristic of each type. Many of these types achieve a constant coverage by varying their dendritic field area inversely with the local density of like-type neighbors. Here we report a population of retinal amacrine cells that do not develop dendritic arbors in relation to the spatial positioning of such homotypic neighbors; rather, this cell type modulates the extent of its dendritic branching when faced with a variable number of overlapping dendritic fields to approximate a uniformity in dendritic density across the retina.     

Effectiveness,Patient Satisfaction,and Cost Reduction of Virtual Joint Replacement Clinic Follow-Up of Hip and Knee Arthroplasty

BackgroundTotal hip and knee arthroplasties are increasingly performed operations, and routine follow-up places huge demands on orthopedic services. This study investigates the effectiveness, patients’ satisfaction, and cost reduction of Virtual Joint Replacement Clinic (VJRC) follow-up of total hip arthroplasty and total knee arthroplasty patients in a university hospital. VJRC is especially valuable when in-person appointments are not advised or feasible such as during the COVID-19 pandemic.MethodsA total of 1749 patients who were invited for VJRC follow-up for knee or hip arthroplasty from January 2017 to December 2018 were included in this retrospective study. Patients were referred to VJRC after their 6-week postoperative review. Routine VJRC postoperative review was undertaken at 1 and 7 years and then 3-yearly thereafter. We evaluated the VJRC patient response rate, acceptability, and outcome. Patient satisfaction was measured in a subgroup of patients using a satisfaction survey. VJRC costs were calculated compared to face-to-face follow-up.ResultsThe VJRC had a 92.05% overall response rate. Only 7.22% required further in-person appointments with only 3% being reviewed by an orthopedic consultant. VJRC resulted in an estimated saving of £42,644 per year at our institution. The patients’ satisfaction survey showed that 89.29% of the patients were either satisfied or very satisfied with VJRC follow-up.ConclusionVJRC follow-up for hip and knee arthroplasty patients is an effective alternative to in-person clinic assessment which is accepted by patients, has high patient satisfaction, and can reduce the cost to both health services and patients.