Blocking FSH induces thermogenic adipose tissue and reduces body fat.

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.

What Mid-term Patient-reported Outcome Measure Scores, Reoperations, and Complications Are Associated with Concurrent Hip Arthroscopy and Periacetabular Osteotomy to Treat Dysplasia with Associated Intraarticular Abnormalities?

BACKGROUND: Periacetabular osteotomy (PAO) is a well-accepted treatment for acetabular dysplasia, but treatment success is not uniform. Concurrent hip arthroscopy has been proposed for select patients to address intraarticular abnormalities. The patient-reported outcomes, complications, and reoperations for concurrent arthroscopy and PAO to treat acetabular dysplasia remain unclear. QUESTIONS/PURPOSES: (1) What are the functional outcome scores among select patients treated with PAO plus concurrent hip arthroscopy at mid-term follow-up? (2) What factors are associated with conversion to THA or persistent symptoms (modified Harris hip score ≤ 70 or WOMAC pain subscore ≥ 10)? (3) What proportion of patients underwent further hip preservation surgery at mid-term follow-up? (4) What are the complications associated with the procedure? METHODS: Between November 2005 and December 2012, 78 patients (81 hips) who presented with symptomatic acetabular dysplasia-defined as a lateral center-edge angle less than 20° with hip pain for more than 3 months that interfered with daily function-had undergone unsuccessful nonsurgical treatment, had associated intraarticular abnormalities on MRI, and underwent combined hip arthroscopy and PAO. Eleven patients did not have minimum 4-year follow-up and were excluded, leaving 67 patients (70 hips) who met our inclusion criteria and had a mean follow-up duration of 6.5 ± 1.6 years. We retrospectively evaluated patient-reported outcomes at final follow-up using the University of California Los Angeles (UCLA) activity score, the modified Harris Hip Score (mHHS), and the WOMAC pain subscore. Conversion to THA or persistent symptoms were considered clinical endpoints. Repeat surgical procedures were drawn from a prospectively maintained database, and major complications were graded according to the validated Clavien-Dindo classification (Grade III or IV). Student t-tests, chi-square tests, and Fisher exact tests identified the association of patient factors, radiographic measures, and surgical details with clinical endpoints. For patients who underwent bilateral procedures, only the first hip was included in our analyses. RESULTS: At final follow-up, the mean mHHS for all patients improved from a mean ± SD of 55 ± 19 points to 85 ± 17 points (p < 0.001), the UCLA activity score improved from 6.5 ± 2.7 points to 7.5 ± 2.2 points (p = 0.01), and the WOMAC pain score improved from 9.1 ± 4.3 points to 3.2 ± 3.9 points (p < 0.001). Three percent (2 of 67) of patients underwent subsequent THA, while 21% (15 of 70) of hips were persistently symptomatic, defined as mHHS less than or equal to 70 or WOMAC pain subscore greater than or equal to 10. Univariate analyses indicated that no patient demographics, preoperative or postoperative radiographic metrics, or intraoperative findings or procedures were associated with subsequent THA or symptomatic hips. Worse baseline mHHS and WOMAC pain scores were associated with subsequent THA or symptomatic hips. Seven percent (5 of 67) of patients underwent repeat hip preservation surgery for recurrent symptoms, and 4% (3 of 67) of patients had major complications (Clavien-Dindo Grade III or IV). CONCLUSION: This study demonstrated that concurrent hip arthroscopy and PAO to treat symptomatic acetabular dysplasia (with intraarticular abnormalities) has good clinical outcomes at mid-term follow-up in many patients; however, persistent symptoms or conversion to THA affected almost a quarter of the sample. We noted an acceptable complication profile. Further study is needed to directly compare this approach to more traditional techniques that do not involve arthroscopy. We do not use isolated hip arthroscopy to treat symptomatic acetabular dysplasia. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Is the Patient-Reported Outcome Measurement Information System Feasible in Bundled Payment for Care Improvement Total Knee Arthroplasty Patients?

BACKGROUND: Several bundled payment plans, like the Bundled Payment for Care Improvement (BPCI) initiative for total joint arthroplasty, have been introduced to decrease costs and improve clinical care. Measuring clinical outcomes with efficient, standardized methodologies is essential to determine the relative value of total joint arthroplasty care. We investigated feasibility and responsiveness of the recently developed Patient-Reported Outcomes Measurement Information System (PROMIS) in total knee arthroplasty (TKA) patients. METHODS: We included patients with preoperative and 1-year PROMIS Physical Function (PF), Pain Interference (PI), and Depression (DEP) scores who received unilateral primary TKA. Burden was assessed using the number of questions and time required for PROMIS completion. The minimum clinically important difference was defined as 5. Floor/ceiling effects were noted if more than 15% of patients responded with the lowest/highest possible score, respectively. Wilcoxon rank-sum test was used to compare categorical data. Analysis of variance was used for PROMIS comparisons. RESULTS: In total, 172 knees (54 BPCI) were included. Floor effects were identified for DEP at baseline (non-BPCI) and follow-up (both groups), and for PI at follow-up only (BPCI). Patients required 140 seconds and 16 questions to answer all 3 PROMIS domains. Sixty-seven percent, 60%, and 44% of knees achieved minimum clinically important difference in PI, PF, and DEP scores respectively, with no significant difference between groups. The BPCI cohort was older (P < .001) with a higher American Society of Anesthesiologists score (P = .028). There were no significant differences in scores between BPCI and non-BPCI patients. CONCLUSION: PROMIS is feasible and time-efficient in BPCI patients undergoing primary TKA. There were no significant differences in outcomes between BPCI and non-BPCI knees. LEVEL OF EVIDENCE: Level III.

Does the Patient-Reported Outcomes Measurement Information System Correlate to Legacy Scores in Measuring Physical Health in Young Total Hip Arthroplasty Patients?

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) was developed by the National Institutes of Health to collect outcome data in rapid dynamic fashion on electronic platforms. The potential role of PROMIS in monitoring pain and function in young total hip arthroplasty (THA) patients has been under-investigated. The purpose of this study is to investigate correlation between PROMIS Physical Function (PF) and PROMIS Pain Interference (PI) and legacy scores with similar considerations. METHODS: We identified 298 hips who underwent primary THA over 40 months. Patients without preoperative PROMIS or legacy scores, or >50 years were excluded. Demographic data included age, gender, and body mass index. Outcome data included PF, PI, modified Harris Hip Score (mHHS), Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) domains, and Short Form 12 components. Floor/ceiling effects were considered to be significant if ≥15% of patients responded with the lowest or highest possible score. Spearman correlation (R) was performed to investigate correlation between legacy scores and PROMIS domains. RESULTS: Mean age was 40 years, mean body mass index was 30.1 kg/m2, and 55% were female. None of the patient-reported outcome measures showed any floor/ceiling effects. PI showed moderate correlation to mHHS (R = -0.60), WOMAC Pain (R = -0.62), and WOMAC PF (R = -0.60). PF showed moderate correlation to mHHS (R = 0.66) and WOMAC PF (R = 0.55). Mean PF and PI scores differed significantly from the general population mean of 50 (36.7, 65.4, respectively; both P < .001). CONCLUSION: PROMIS is an attractive alternative to legacy scoring measures, showing moderate correlations between PROMIS physical domains and legacy PROMs of WOMAC and mHHS in young patients undergoing THA.

Patients With Symptomatic Sequelae of Slipped Capital Femoral Epiphysis Have Advanced Cartilage Wear at the Time of Surgical Intervention.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) is a common hip problem in children. The resulting deformity can cause impingement similar to cam-type idiopathic femoroacetabular impingement (FAI). Although there are similarities between FAI and SCFE, deformity patterns, severity, and time of onset of symptoms varies, which may impact management. The purpose of this study was to describe patterns of articular cartilage damage in patients undergoing surgical hip dislocation for sequelae of SCFE in comparison to patients undergoing arthroscopic surgery for primary FAI. METHODS: Patients were identified who underwent surgical treatment for hip pain due to primary FAI (cam type) or sequelae of SCFE. Clinical data and radiographic measurements were recorded. Cartilage was assessed intraoperatively. Severity was classified using the modified Beck classification, while location was classified into 6 sectors. Statistical analysis was performed to test for differences in demographic and radiographic characteristics between the SCFE and FAI patients. χ2 or Fisher exact tests were used to evaluate trends in patterns of acetabular and femoral cartilage wear between SCFE and FAI groups. RESULTS: The SCFE group had 28 hips compared with 304 in the FAI group. SCFE patients were younger (19 vs. 32, P<0.001), had higher body mass index (30±5.9 vs. 24±4.8, P<0.001), and were more often male (61% vs. 27%, P<0.001). Deformity severity based on α-angle was higher in the SCFE group [AP 74 vs. 55 (P=0.001) and Dunn 72 vs. 58 (P<0.001)]. There were no significant differences with regards to lateral center edge angle, anterior center edge angle, or Tonnis angle. In both groups the most common locations for cartilage lesions in both groups were the anterior peripheral and superolateral peripheral regions with fewer but more widely distributed femoral head lesions. The SCFE group had higher rates of femoral head and superolateral central cartilage lesions compared with the FAI group. There was no statistical difference between high-grade femoral or acetabular cartilage lesions between groups. CONCLUSIONS: Patients with SCFE were younger at the time of surgery and presented with more severe deformity based on radiographic α-angle compared to patients with FAI. Our results suggest higher prevalence of femoral head lesions and more diffuse cartilage injury in patients with SCFE. This study can be used to support early surgical intervention in patients with symptomatic sequelae of SCFE due to risk of premature joint damage. LEVEL OF EVIDENCE: Level III-prognostic study.

FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness.

Fibrous sheath interacting protein 1 (FSIP1), a spermatogenesis-related testicular antigen, is expressed in abundance in breast cancers, particularly in those overexpressing human epidermal growth factor receptor 2 (HER2); however, little is known about its role in regulating the growth and metastasis of breast cancer cells. We and others have shown previously that FSIP1 expression in breast cancer correlates positively with HER2-positivity, recurrence, and metastases and negatively with survival. Here, using coimmunoprecipitation and microscale thermophoresis, we find that FSIP1 binds to the intracellular domain of HER2 directly. We further show that shRNA-induced FSIP1 knockdown in SKBR3 and MCF-7 breast cancer cells inhibits proliferation, stimulates apoptosis, attenuates epithelial-mesenchymal transition, and impairs migration and invasiveness. Consistent with reduced proliferation and enhanced apoptosis, xenotransplantation of SKBR3 cells stably transfected with sh-FSIP1 into nu/nu mice results in reduced tumor volumes compared with sh-NC transplants. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping using sh-FSIP1 gene signature yielded associations with extracellular matrix protein pathways, and a reduction in SNAI2 protein expression was confirmed on Western blot analysis. Complementarily, interrogation of the Connectivity Map using the same gene signature yielded, as top hits, chemicals known to inhibit epithelial-mesenchymal transition, including rapamycin, 17-N-allylamino-17-demethoxygeldanamycin, and LY294002. These compounds phenocopy the effects of sh-FSIP1 on SKBR3 cell viability. Thus, FSIP1 suppression limits oncogenesis and invasiveness in breast cancer cells and, considering its absence in most other tissues, including normal breast, may become a potential target for breast cancer therapy.

Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11ß-hydroxysteroid dehydrogenase type 2 deficiency.

Mutations in 11ß-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) cause an extraordinarily rare autosomal recessive disorder, apparent mineralocorticoid excess (AME). AME is a form of low renin hypertension that is potentially fatal if untreated. Mutations in the HSD11B2 gene result either in severe AME or a milder phenotype (type 2 AME). To date, ∼40 causative mutations have been identified. As part of the International Consortium for Rare Steroid Disorders, we have diagnosed and followed the largest single worldwide cohort of 36 AME patients. Here, we present the genotype and clinical phenotype of these patients, prominently from consanguineous marriages in the Middle East, who display profound hypertension and hypokalemic alkalosis. To correlate mutations with phenotypic severity, we constructed a computational model of the HSD11B2 protein. Having used a similar strategy for the in silico evaluation of 150 mutations of CYP21A2, the disease-causing gene in congenital adrenal hyperplasia, we now provide a full structural explanation for the clinical severity of AME resulting from each known HSD11B2 missense mutation. We find that mutations that allow the formation of an inactive dimer, alter substrate/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect disruption of substrate binding or mildly alter intramolecular interactions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes of an extremely rare monogenic disorder.

Is the Patient-Reported Outcome Measurement Information System Feasible in Bundled Payment for Care Improvement in Total Hip Arthroplasty Patients?

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) is increasingly used to assess patient health. The Bundled Payment for Care Improvement (BPCI) initiative for total hip arthroplasty (THA) was introduced to decrease costs and improve clinical care. We investigated differences between BPCI and non-BPCI THA patients and their PROMIS scores, along with its feasibility and responsiveness in these populations. METHODS: We included all consecutive patients receiving unilateral primary THA who also had preoperative and one-year postoperative PROMIS physical function (PF), PROMIS pain interference (PI), and PROMIS depression (DEP) scores. Demographics and PROMIS scores were compared. Test burden was assessed using the number of questions and time required for PROMIS completion. The minimum clinically important difference was defined as 5. Floor and ceiling effects were noted if more than 15% of patients responded with the lowest or highest possible score, respectively. Wilcoxon rank-sum test was used to compare categorical data. ANOVA was used for PROMIS comparisons. RESULTS: 290 hips (86 BPCI, 30%) were included. The BPCI cohort was older (P < .001) with a higher American Society of Anesthesiologists physical status classification system (P = .0045). There were significant differences in baseline scores of PF and DEP between BPCI and non-BPCI (P = .046 and P = .048, respectively). Both groups showed significant improvement at follow-up in all scores (all P < .001). Significantly more non-BPCI patients achieved minimum clinically important difference at follow-up in PI and PF (P = .047 and P = .023, respectively). Floor effects were identified for DEP at baseline and follow-up and for PI at follow-up only. CONCLUSION: PROMIS is feasible and time-efficient in BPCI patients undergoing primary THA. There were significant differences between BPCI and non-BPCI hips. LEVEL OF EVIDENCE: Level III.

Surgical Perfusion and Isolation of the Porcine Pancreas for Islet Isolation.

Pancreatic islet transplantation is an emerging treatment for type I diabetes; however, it is limited by donor matching and availability. Porcine islet xenotransplantation offers a promising alternative to allotransplantation, with the potential for large-scale production of on-demand, functional islets. The yield and viability of isolated islets is highly susceptible to the quality of the donor pancreas and the method of procurement, particularly the duration of warm-ischemia time. To improve organ preservation and subsequent islet yield and viability, we have developed a protocol for surgical perfusion and resection of the porcine pancreas. This protocol employs direct infrarenal aortic cannulation and organ perfusion to both minimize warm-ischemia time and simplify the procedure for operators who do not have extensive surgical expertise. Subsequent arterial perfusion of the pancreas via the aorta flushes stagnant blood from the microvasculature, thereby reducing thrombosis and oxidative damage to the tissue. This manuscript provides a detailed protocol for surgical perfusion and resection of the porcine pancreas, followed by islet isolation and purification.

Does the Patient-Reported Outcomes Measurement Information System Correlate to Legacy Scores in Measuring Mental Health in Young Total Hip Arthroplasty Patients?

Background: Mental health is becoming increasingly important in patient outcomes. The patient reported outcome measurement information system (PROMIS) was developed by the NIH to collect outcome data in rapid dynamic fashion on electronic platforms. The potential role of PROMIS in monitoring young total hip arthroplasty (THA) patients is under-investigated. The purpose of this study is to investigate correlations between PROMIS Depression or Anxiety with SF-12 mental component score. Methods: We identified 223 hips (200 patients) who underwent primary THA over a 30-month period at a single institution. Patients without preoperative PROMIS or SF-12 mental scores, or >50yo were excluded. All data was collected preoperatively and included age, sex, BMI, ASA, PROMIS Depression, PROMIS Anxiety, and SF-12 Mental component score. We considered floor and ceiling effects as significant if >15% of patients responded with the lowest or highest possible score, respectively. Relationships between SF-12 and PROMIS were investigated using correlation (R), and were considered strong if R>0.7. Results: Mean age was 41-years-old, mean ASA category was 2, mean BMI was 30kg/m2, and 54% were female. None of the PROMs showed any floor/ceiling effects at baseline. PROMIS Depression showed a strong correlation to SF-12 Mental (R=-0.72) while PROMIS Anxiety showed a moderate correlation to SF-12 Mental (R=-0.58). Negative linear relationships were observed because a lower PROMIS Depression/Anxiety values indicates less depressive/anxious feelings (inverse of SF-12). Conclusion: PROMIS Anxiety and Depression correlate well with SF-12 mental. These PROMIS domains may be attractive alternatives to legacy mental health instruments in young THA patients. Level of Evidence: III.

Factors Associated With Disease Progression in the Contralateral Hip of Patients With Symptomatic Femoroacetabular Impingement: A Minimum 5-Year Analysis.

BACKGROUND: Femoroacetabular impingement (FAI) is one of the most common causes of hip osteoarthritis, yet the factors controlling disease progression are poorly understood. PURPOSE: To investigate rates of initial and subsequent symptoms in the contralateral hip of patients with FAI, and identify predictors of disease progression (symptom development and surgical intervention) in the contralateral hip. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This prospective study included a minimum 5-year follow-up of the contralateral hip in 179 patients undergoing FAI surgery. Symptoms (moderate pain) and surgical progression were monitored. Univariate and multivariate analyses compared patient-specific and imaging characteristics of symptomatic patients with those who remained asymptomatic to identify factors associated with disease progression. RESULTS: A total of 150 patients (84% follow-up) were followed for a mean of 7.1 years (range, 5-11 years). Thirty-nine of these patients (26% [39/150]) had contralateral hip symptoms at initial evaluation. Of those without contralateral hip symptoms at initial evaluation, 32% (36/111) had developed contralateral hip symptoms by latest follow-up. Those who developed symptoms during the study period had a lower anteroposterior head-neck offset ratio (0.153 vs 0.165; P = .005), decreased total arc of rotation in 90° of flexion (39.9° vs 51.1°; P = .005), and decreased external rotation in 90° of flexion (28.6° vs 37.1°; P = .003) compared with those who never developed symptoms. Age, sex, body mass index, alpha angle, lateral center-edge angle, internal rotation in flexion, and University of California, Los Angeles (UCLA), activity score were similar between these groups. Those with contralateral symptoms at initial evaluation progressed to contralateral surgery at a rate of 41% (16/39) and those who developed contralateral symptoms during the study period progressed to contralateral surgery at a rate of 28% (10/36). Among those with contalateral hip symptoms (either present initially or developed during study period)), younger age (24.6 vs 34.1 years; P < .001) and baseline UCLA activity score ≥9 (P = .003) were associated with progression to surgery. By Kaplan-Meier analysis, 64%, 54%, and 48% of patients remained free of contralateral hip symptoms at 2, 5, and 10 years. CONCLUSION: At a mean follow-up of 7.1 years, significant symptoms in the contralateral hip of patients with FAI were present in approximately 50% of patients. FAI disease progression (symptom development and surgical intervention) was associated with decreased hip rotation arc, decreased external rotation, and decreased head-neck offset ratio. In symptomatic patients, younger age and UCLA activity score ≥9 were associated with progression to surgery. These findings represent important factors for patient counseling and risk modeling in FAI.

Mid-Term Outcomes of Combined Hip Arthroscopy and Limited Open Capsular Plication in the Non-Dysplastic Hip.

BACKGROUND: Hip microinstability remains poorly-defined but increasingly diagnosed in the setting of borderline dysplasia (LCEA 20-25°), soft tissue laxity, or following unrepaired arthroscopic capsulotomy. While hip microinstability is com-monly treated with arthroscopic capsular plication with short-term outcomes reported, this procedure has been performed open for some time. The purpose of current study was to assess the durability of outcomes of combined arthroscopy and open capsular plication in treating symptomatic hip microinstability at mid-term follow-up. METHODS: We retrospectively identified hips that underwent combined hip arthroscopy and open capsular plication for symptomatic microinstability between 2008 and 2013. Hips with excessive femoral anteversion (femoral version >35°) or classic acetabular dysplasia (LCEA <20°) were treated with bony reorientation and were not included in the current study. Patient reported outcomes scores were collected preoperatively and at a minimum five year follow-up. Hips that required reoperation or did not meet criteria for minimally clinically important difference (MCID, ≥8 increase in mHHS) or patient acceptable symptom scores (PASS, mHHS) were considered failures. RESULTS: A total of 27 hips met criteria for inclusion and follow-up was obtained for 22 hips (81.5%) at a mean of 7.1 years. All patients were female with a mean age of 25.9 years and 7 (32%) hips had previous surgery. Patients undergoing the combined procedure improved from a mean baseline mHHS of 55.3±13 to a mean follow-up mHHS of 74.5±20.9 (p<0.001). At midterm follow-up, 54.5% of hips met criteria for PASS and 68.2% of hips met criteria for MCID, with 72.7% of hips meeting criteria for either MCID or PASS. Overall, 10 hips (45%) were considered failures with 6 hips (27%) requiring reoperation and an additional 4 hips (18%) with clinical failure. Hips without previous surgery had a failure rate of 33.3% (5/15) while 71.4% (5/7) of those with previous surgery failed (P=.09). CONCLUSION: Our study demonstrates a high (45%) rate of reoperations and persistent symptoms in hips with microinstability treated with combined arthroscopy and open capsular plication. Further mid- and long-term studies evaluating soft tissue plication are needed, as well as comparisons with bony procedures in the setting of microinstability are needed.Level of Evidence: III.

The burden and utility of routine follow-up at one year after primary arthroplasty.

AIMS: Routine surveillance of primary hip and knee arthroplasties has traditionally been performed with office follow-up visits at one year postoperatively. The value of these visits is unclear. The present study aims to determine the utility and burden of routine clinical follow-up at one year after primary arthroplasty to patients and providers. METHODS: All patients (473) who underwent primary total hip (280), hip resurfacing (eight), total knee (179), and unicompartmental knee arthroplasty (six) over a nine-month period at a single institution were identified from an institutional registry. Patients were prompted to attend their routine one-year postoperative visit by a single telephone reminder. Patients and surgeons were given questionnaires at the one-year postoperative visit, defined as a clinical encounter occurring at nine to 15 months from the date of surgery, regarding value of the visit. RESULTS: Compliance with routine follow-up at one year was 35%. The response rate was over 80% for all questions in the patient and clinician surveys. Overall, 75% of the visits were for routine surveillance. Patients reported high satisfaction with their visits despite the general time for attendance, including travel, being over four hours. Surgeons found the visits more worthwhile when issues were identified or problems were addressed. CONCLUSION: Patient compliance with follow-up at one year postoperatively after primary hip and knee is low. Routine visits of asymptomatic patients deliver little practical value and represent a large time and cost burden for patients and surgeons. Remote strategies should be considered for routine postoperative surveillance primary hip and knee arthroplasties beyond the acute postoperative period. Cite this article: Bone Joint J 2020;102-B(7 Supple B):85-89.

Targeting vascular endothelial growth factor ameliorates PMMA-particles induced inflammatory osteolysis in murine calvaria.

Cytokines and growth factors mediate inflammatory osteolysis in response to particles released from bone implants. However, the mechanism by which this process develops is not entirely clear. Blood vessels and related factors may be required to deliver immune cells and soluble factors to the injury site. Therefore, in the current study we investigated if, vascular endothelial growth factor (VEGF), which is required for angiogenesis, mediates polymethylmethacrylate (PMMA) particles-induced osteolysis. Using bone marrow derived macrophages (BMMs) and ST2 stromal cell line, we show that PMMA particles increase VEGF expression. Further, using a murine calvarial osteolysis model, we found that PMMA injection over calvaria induce significant increase in VEGF expression as well as new vessel formation, represented by von Willebrand factor (vWF) staining. Co-treatment using a VEGF-neutralizing antibody abrogated expression of vWF, indicating decreased angiogenesis. Finally, VEGF neutralizing antibody reduced expression of Tumor necrosis factor (TNF) and decreased osteoclastogenesis induced by PMMA particles in calvariae. This work highlights the significance of angiogenesis, specifically VEGF, as key driver of PMMA particle-induced inflammatory osteolysis, inhibition of which attenuates this response.

New developments in prenatal diagnosis of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations in the CYP21A2 gene. Females affected with classical CAH are at risk for genital ambiguity, but can be treated in utero with dexamethasone before 9 gestational weeks to prevent virilization. Early genetic diagnosis is unavailable through current invasive methods of chorionic villus sampling and amniocentesis. New developments in prenatal genetic testing utilize fetal DNA extracted from maternal blood through noninvasive methods, which allow the determination of fetal gender and the diagnosis of CAH at an early gestational age (<9 weeks). Noninvasive prenatal diagnosis allows for the establishment of early and effective management plans in fetuses at risk for CAH and avoids unnecessary prenatal dexamethasone treatment.

NFAT2 is an essential mediator of orthopedic particle-induced osteoclastogenesis.

Particle-induced periprosthetic osteolysis is the major cause for orthopedic implant failure. This failure is mediated mainly by the action of osteoclasts, the principal cells responsible for bone resorption and osteolysis. Therapeutic interventions to alleviate osteolysis have been focused on understanding and targeting mechanisms of osteoclastogenesis. The nuclear transcription factor NFAT is an essential terminal differentiation factor of osteoclastogenesis. This transcription factor is known to cooperate with c-jun/AP-1 in mediating RANKL-induced osteoclastogenesis. We have previously determined that RANKL is an essential cytokine mediator of particle-induced osteoclastogenesis, and that PMMA particles activate JNK and c-jun/AP-1 in bone marrow macrophages (osteoclast precursors). In the current study, we investigated the effect of PMMA particles on the NFAT signaling pathway in osteoclast precursor cells. Our findings point out that PMMA particles stimulate nuclear translocation of NFAT2 in wild-type osteoclast precursors, which is associated with increased osteoclastogenesis. More importantly, induction of osteoclastogenesis was selectively blocked in a dose-dependent fashion by the calcineurin inhibitors, Cyclosporine-A and FK506. Further, this activation was also blocked in a time-dependent fashion by the NFAT inhibitor VIVIT. Finally, we provide novel evidence that PMMA particles induce binding of NFAT2 and AP-1 proteins. Thus, our findings demonstrate that activation of the NFAT pathway in conjunction with MAP kinases is essential for basal and PMMA-stimulated osteoclastogenesis.