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Central estrogen signaling in the medial basal hypothalamus (MBH) coordinates energy expenditure, food intake, and reproduction, as well as skeletal homeostasis. Prior work from our lab found that estrogen signaling via Estrogen Receptor alpha (ERa) in the arcuate (ARC) nucleus normally restrains bone formation in female mice only. We asked if the high bone mass in the Esr1Nkx2-1Cre mouse model, which ablates ERa in the MBH, is maintained or deteriorates with chronic overnutrition, as this is known to increase bone frailty in humans. To carry out this study, Esr1Nkx2-1Cre mutant female mice were fed HFD (Research Diets, D12492, 60% fat) or chow (SCD, 5058; LabDiet, 4% fat) for 17 weeks beginning at 10 weeks of age and housed at 22C. Although neither cohort gained significant weight on HFD nor exhibited marked changes in other metabolic parameters (%fat, GTT, ITT, etc.), this dietary challenge reversed and normalized the high bone mass in mutant females. Specifically, the ratio of BV/TV in the distal femur decreased dramatically from 36% to 6%, as measured by 3D-microcomputed tomography (micro-CT); cortical bone also decreased similarly. For comparison, control females fed HFD showed a non-significant decrease in bone mass (4.9% to 3.9% BV/TV). Unexpectedly, the large drop in bone mass in Ers1Nkx2-1Cre females fed HFD was uncoupled from an increase in bone marrow adipose tissue (BMAT). In contrast, control cohorts showed a marked 9-fold increase in BMAT following HFD. Thus, the high bone mass in mutant Ers1Nkx2-1Cre females, which persists in aged and estrogen-depleted females, quickly disintegrates with a dietary challenge. Recent RNA-Seq data from microdissected ARC tissue reveals several secreted factors that are dramatically elevated in mutant females but drop 10-20-fold after HFD. Current studies are underway to ask if these candidate factors from the ARC impact bone mass or the osteogenic capacity of skeletal stem cells. Our findings are in stark contrast to the notion that dietary excess reduces bone health by increasing bone fat at the expense of osteogenesis. Instead, based on our model, we posit that dietary excess directly determines dynamic bone remodeling by acting on the brain.

ENDO 2022

Brain Determinants of Dynamic Bone Remodeling in Females

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

technical paper

Female athletes with low energy availability are at risk for impaired bone microarchitecture and strength associated with hypogonadism. Data are lacking for bone outcomes in male athletes. We studied 31 men 16-30 years (n=15 runners with mean (±SD) mileage 43±4 miles/week, n=16 non-athlete controls). We assessed distal tibia and radius volumetric BMD (vBMD) and microarchitecture by high resolution peripheral quantitative CT (HRpQCT), estimated bone strength by microfinite element analysis and body composition by DXA. Testosterone, estradiol (by LC-MS) and leptin (by electrochemiluminescence) were measured. Groups did not differ for mean age (24.5±3.6y), BMI (22.2±2.6 kg/m²), lean mass, or testosterone or estradiol levels. Mean tibial cortical vBMD was lower and porosity higher in athletes than controls (p<0.01). In contrast, mean tibial trabecular vBMD and number were higher, and separation lower, in athletes (p<0.02). Athletes with BMI ≤ 21 kg/m² had lower tibial failure load (bone strength estimate) than those with BMI >21 kg/m² (p=0.007). Lean mass (R=0.85, p<0.0001), serum leptin (R=0.59, p=0.046) and estradiol (R=0.66, p=0.007), but not testosterone, were associated with tibial failure load in athletes. Athlete and control groups did not differ for HRpQCT variables at the radius. Despite weight-bearing activity, male runners have impaired tibial cortical BMD and microarchitecture, which may increase their risk for bone stress injuries. Lower leptin (reflecting lower fat mass) and estradiol (converted from testosterone in adipose tissue), as well as lean mass, are determinants of lower tibial strength in these athletes, suggesting that low energy availability is a risk factor for impaired bone strength in male runners.

Male Runners Have Impaired Tibial Cortical Bone Integrity and Strength Compared to Non-athletes

Background: Primary hyperparathyroidism (PHPT) is one of the known causes of secondary osteoporosis. PHPT is associated with increased bone turnover, low bone density and quality; but there have been conflicting results on the risk of fractures. There is limited information on the effects of age, gender, and ethnicity on fracture risk in PHPT.
Objective: To determine the prevalence of vertebral fractures (VFx) and associated risk factors in patients with PHPT
Design: Retrospective cross-sectional study
Setting: Academic medical center in a community setting
Main outcome measured: 1) Bone mineral density (BMD), and T- and Z-scores of the lumbar spine (LS). 2) Vertebral morphometry was assessed using the Genant method to identify asymptomatic vertebral fractures (VFx) on CT spine images. 3) Biochemical measurements included serum PTH, Creatinine (Cr) and Calcium (Ca).
Results: In this retrospective study of consecutive 560 PHPT patients verified by surgery [447 women with a median age of 62y; 362 Caucasians (65%), 142 African Americans (AA, 25%) and 22 unspecified race (10%)] were included. Prevalence of VFx was 13% (n=75), other sites 15% (n=84), wrist fractures 3% (n=16) and hip fractures 1% (n=6). Fracture prevalence at all sites was higher in women, but significant only for VFx (71% vs 29%, p=0.04). In subgroup analysis by age (above or below 50y) and gender, there was no significant difference in LS BMD, T- or Z-score values, serum PTH, Ca and Cr in patients with and without VFx. In subgroup analysis by ethnicity: i) prevalence of all fractures was higher in Caucasians compared to AA and others ii) mean serum PTH (±SD) level was significantly higher in AA vs Caucasian patients with VFx (190 ± 124 vs 121 ± 57 pg/mL, p=0.03) and iii) no significant differences were noted in LS BMD, T-or Z-scores, serum Ca and Cr in patients with VFx.
In multivariate analysis (age, serum Ca, PTH >100, and LS BMD) to predict risk of VFx in all patients, only age [OR 1.07, CI 1.03-1.11) and serum Ca [OR 1.7, CI 1.03 – 2.79] were significant factors. In women, multivariate analysis identified increasing age to be the only significant risk factor to predict risk of VFx. [OR 1.107, CI 1.03-1.12].
Conclusion: Vertebral fractures (VFx) is more prevalent in comparison to wrist and hip fractures in patients with PHPT. Serum PTH is significantly higher in African American PHPT patients with VFx. Increasing age and serum calcium ≥11.1 mg/dL are significant predictors of VFx in PHPT patients.

Effect of Age, Gender, & Ethnicity on the Prevalence of Vertebral fractures in Patients with Primary Hyperparathyroidism

Introduction: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder of progressive heterotopic ossification, resulting in cumulative loss of joint function and severe disability. We present results from an international, cross-sectional FOP Burden of Illness Survey (NCT04665323) demonstrating the impact of loss of joint function on quality of life (QoL) for patients and their family members. Methods: Individuals with FOP (survey proxy-completed for patients aged <13 years), their primary caregivers, and other family members (aged ≥18 years) were eligible to participate. Family members who acted as a proxy could also participate themselves, as a family member. The survey was available online from 18Jan21–30Apr21 in 15 countries and 11 languages. The Patient­-Reported Mobility Assessment (PRMA) evaluated range of motion across 12 joints and 3 body regions (total scores range from 0–30; higher scores reflect more severe limitations). PRMA total scores were categorized into four Levels: Level 1, 0–6; Level 2, 7–12; Level 3, 13–18; Level 4, ≥19. To assess the impact of FOP on QoL, patients ≥13 years and their family members completed the EuroQoL health-related QoL questionnaire (EQ-5D-5L; index ranges from <0 [worst health] to 1 [full health]). Descriptive analyses of EQ-5D-5L index scores were performed for each population and by patients' PRMA Level. Linear regression analyses (adjusted for geographic region) were used to evaluate the relationship between patients' degree of joint impairment (PRMA total score) and patient or family member EQ-5D-5L index score. Results: 463 survey responses were received from 405 individuals: patient/proxy population, n=219 (patients ≥13 years, n=161; proxies for patients <13 years, n=58); family member population, n=244, of whom 163 identified as primary caregivers. Mean (standard deviation [SD]) EQ-5D-5L index score was 0.24 (0.36) for patients ≥13 years, 0.83 (0.22) for primary caregivers, and 0.85 (0.21) across all family members. For the patient population, mean (SD) EQ-5D-5L index score decreased as PRMA Level increased: Level 1, 0.61 (0.26); Level 2, 0.46 (0.34); Level 3, 0.21 (0.30); Level 4, 0.05 (0.26). There was a significant negative association between PRMA total score and EQ­-5D-5L index score for patients, such that for every 1-unit increase in the PRMA total score of the patient, there was a mean (standard error [SE]) decrease of 0.029 (0.003; p<0.0001) in EQ-5D-5L adjusted for geographic region. For all family members, there was no significant association between EQ-5D-5L and the PRMA total score of the patient (p=0.6737). Conclusion: Loss of joint function (as represented by PRMA Level) has a significant, detrimental impact on QoL for patients with FOP. These findings increase understanding of the impact of FOP on patients and their family members, and may help to improve quality of care and access to support for the FOP community. Funding: Sponsored by Ipsen.

Joint Function and Quality of Life in Fibrodysplasia Ossificans Progressiva: Results from an International Burden of Illness Survey of Patients and Family Members

Background: Hypercalcemia during pregnancy is rare. The true incidence, however, is difficult to estimate as routine calcium screening is not recommended. Hypercalcemia is linked with various maternal and fetal outcomes but overall, the literature is conflicting.
Aims: Aim of this study is to determine the frequency of hypercalcemia in pregnancy and to determine association with early maternal and fetal outcomes.
Methods: This retrospective cohort study included all confirmed gestations with expected date of delivery (EDD) between 2017-2019 at a large tertiary maternity unit. Baseline demographic, biochemical, and clinical data collected as part of a clinical-administrative dataset was retrieved. Maternal and fetal outcomes studied were incidence of fetal loss (miscarriage/stillbirth), pre-term delivery, emergency C-section, hypertension, blood loss during delivery, neonatal intensive care unit (NICU) admission, and fetal birth weight (for term deliveries).
Results: Total number of gestations and livebirths recorded between 2017-2019 were 33,118 and 20,969, respectively, with median age of 30.1 [IQR 25.6-34.3] years. Two-thirds of pregnancies were in Caucasian women (65.9%) followed by Asians (9.6%), Afro-Caribbean (5%), and others (19.5%). 15.7% (n=5195) of all gestations had calcium tested in the preceding ten months of EDD. Of these, the hypercalcemia and hypocalcemia were noted in 42 (0.81%) and 499 gestations (9.61%) respectively. The median adjusted calcium in the hypercalcemic group was 2.75 mmol/L [IQR 2.65-2.88] and underlying diagnoses were primary hyperparathyroidism (n=17), transient hypercalcemia (n=12), suspected familial hypocalciuric hypercalcemia (n=2), sarcoidosis (n=1), and unknown (n=10). Of maternal and fetal outcomes, the incidence of pre-term delivery (20.0% v 9.2%; P=0.042), emergency C-section (42.4% v 21.4%; P=0.021), neonatal intensive care unit (NICU) admission (19.4% v 8.2%; P=0.024), and blood loss during delivery (1252 v 526 mL; P<0.001) was higher in the hypercalcemic group. The incidence of fetal loss (22.5% v 18.9%; P=0.560) and hypertension (0% v 1%; P =0.561) was not different between hyper and normocalcemic groups. Interestingly, the hypocalcemic group also demonstrated higher incidence of pre-term delivery (24.2% v 9.2%; P=<0.001), emergency C-section (28.6% v 21.4%; P=0.025), NICU admission (15.9% v 8.2%; P<0.001), and blood loss (627 v 526 mL; P<0.001), but not of fetal loss (21.0% v 18.9%; P=0.281) or hypertension (2.2% v 1.0%; P =0.054) compared to the eucalcemic group.
Conclusion: The incidence of hypercalcemia in pregnancy is low (0.81%). However, abnormal calcium levels are associated with worse maternal and fetal outcomes. Research needs to focus on whether routine calcium estimations are necessary and if treatment of these conditions improves maternal and fetal outcomes. We recommend that calcium testing should be considered in women who are at risk of worse outcomes during current or previous pregnancies.

Hypercalcemia and hypocalcemia during pregnancy are associated with worse maternal and fetal outcomes

Introduction
We used a machine-learning algorithm (gradient boosting) to test the association of genetic risk for 11 glycemic traits with osteoporosis and fractures in the UK Biobank population.
Methods
The study was performed with 409,633 caucasian participants in the UKBIobank. We identified 4626 SNPs associated with 11 glycemic traits from the NGHRI catalogue for GWAS studies. Weighted genetic risk scores (wGRS) were calculated using the effect estimates from the GWAS studies. We used a gradient-boosting machine-learning (GBM) model to identify the relative influence (RI) of baseline variables and wGRS of the glycemic traits on osteoporosis and all-cause fractures in the UK Biobank population. We split the data into training (2/3) and testing set (1/3) and calculated the discriminatory power of the models using the area under the curve (AUC) with the testing model.
Results
The study consisted of 409,633 individuals (53% females) with a median age of 58 (51-63) years and a median BMI of 26.7 (24.1-29.8) kg/m². The study population had 41954 (10.2%) all-cause fractures and 4995 (1.2%) participants with osteoporosis. In the GBM model, top wGRS associated with all-cause fractures were wGRS for Type 1 diabetes (RI=4.49) and fasting glucose (4.17). In contrast, the top wGRS associated with osteoporosis were wGRS for acute insulin response to glucose (RI=6.74) and Type 1 diabetes (RI=5.62). Both models showed low to moderate discriminatory power with the area under the AUC of 0.57(CI: 0.56-0.57) for fractures and 0.75(CI: 0.74-0.76) for osteoporosis.
Conclusion
We showed a differential effect of wGRS for various glycemic traits on the risk of fractures and osteoporosis in the UK Biobank population. However, the machine-learning model with wGRS for glycemic traits demonstrated limited capacity to predict fractures and osteoporosis in the general population.

Estimating the relative influence (RI) of genetic risk of 11 glycemic traits on osteoporosis and fractures in 409633 participants in the UK Biobank using Machine learning

Purpose: Metabolic syndrome (MetS) comprises a constellation of risk factors for cardiovascular disease, which are thought to be derived from truncal obesity. Adipose tissue can have positive effects on bone density through mechanical stimulation on weight bearing sites and can have hormonal influences which affect bone cells, however in obesity this relationship is inversed as the deleterious effects of excess fat mass predominate. It is unclear how MetS and the regional distribution of fat relate with bone density and bone quality in lean individuals who do not benefit from increased weight bearing.
Methods: We performed a cross sectional analysis of adults who underwent bone density and body composition by dual energy x-ray absorptiometry (DXA) at a university health system bone clinic, and had laboratory and demographic data available in the electronic medical record. We included adults with BMI below 24.9 kg/m2 in the analysis. Individuals were classified as being metabolically unhealthy lean (MUL) when they fulfilled at least 2 of the following criteria: blood pressure > 130/85, triglyceride >150 mg/dL, HDL < 50 mg/dL for women and < 40 mg/dL for men, fasting plasma glucose >100mg/dL (or HbA1c >=5.7), and metabolically healthy lean (MHL) when they did not fit the criteria. Linear regression was used to evaluate the association of body composition fat parameters with trabecular bone score (TBS), and bone mineral density (BMD) at the total hip (TH).
Results: Among the 119 (100%) lean adults, 50 (42%) were classified as being MUL. Mean age was 62 ±14 years old and mean BMI was 22 ±1.9kg/m2. The population was mostly white 105 (88%) and 70 (41%) were Hispanics. Additionally, 43 subjects (40%) had a history of a previous fracture. Total body fat was similar between the two groups (mean,%) MHL 33.5, MUL 34.1 (p=0.32), as were age (mean, years) MHL 62.3 vs MUL 62.5 (p=0.48), BMI (mean, kg/m2) MHL 22.2, MUH 22.2 (p=0.49), TH BMD (mean, g/cm2) MHL 0.74, MUL 0.72 (p=0.140) and TBS (mean, unitless) MHL 1.34, MUL 1.33 (p=0.308). However, visceral adipose tissue area (VAT) (mean, cm2) was statistically significantly different between the groups (MHL 69.0, MUL 86.7, p=0.004). In linear regression analyses total body fat had negative association with TBS (B=-0.44, p<0.001) and TH BMD (B= -0.37, p<0.001) while VAT had negative association with TBS (B=-0.26, p=0.02) but not TH BMD (B=-0.17, p=0.08).
Conclusion: In our sample of older lean individuals body fat distribution varied by classification of metabolic health. Total body fat amount was associated with decreasing bone density and quality, while higher truncal fat as measured by VAT area was associated with decreasing bone quality. Our findings suggest that excess body fat may have deleterious effects on bone health even in lean individuals

Bone Quality in Lean Adults with Metabolic Syndrome

While anorexia nervosa is associated with impaired skeletal integrity, less is known about the skeletal effects of atypical anorexia nervosa, in which psychological criteria for anorexia nervosa are met, but affected individuals are not low weight. Mean bone mineral density (BMD) is higher in atypical anorexia nervosa than in low-weight anorexia nervosa but lower than in healthy controls. However, it is unknown whether bone microarchitecture and strength are affected. We hypothesized that bone microarchitecture and estimated strength would be impaired in women with atypical anorexia nervosa.
This was a cross-sectional study of women ages 21-46 years (n=55): n=28 with atypical anorexia nervosa (body mass index (BMI) >18.5 kg/m²), n=27 healthy, normal weight, eumenorrheic controls. Exclusion criteria included use of oral contraceptives. Areal BMD (aBMD) was assessed by DXA. Volumetric BMD (vBMD), microarchitecture, and failure load (a bone strength estimate) at the distal tibia and radius were assessed by high-resolution peripheral quantitative CT.
Median(IQR) BMI was lower [19.4(18.6,20.2) vs 22.2(21.5,23.0), p<0.0001] and median serum 25OH vitamin D level was higher [31(24,39) vs 22(17,25), p=0.0001] in atypical anorexia nervosa than healthy controls. In the atypical anorexia nervosa group, 89% had a history of low weight, 21% had a history of overweight/obesity, 31% had current amenorrhea, and 88% had a history of amenorrhea; median duration of anorexia nervosa was 11(5,14) years.
Median lateral spine, total hip, femoral neck, and total radius aBMD Z-scores were lower in atypical anorexia nervosa than healthy controls [lateral spine: -1.1(-2.0,-0.1) vs -0.4(-0.7,0.4), total hip: -0.8(-1.3,0.2) vs 0.2(-0.4,0.7), femoral neck: -0.9(-1.4,0.1) vs -0.1(-0.9,0.6), radius: -0.2(-0.9,0.3) vs 0.1(-0.4,0.6); p≤0.04 for all]. At the tibia, median total, cortical, and trabecular vBMD; cortical thickness; trabecular bone volume fraction; and failure load were lower in atypical anorexia nervosa than healthy controls (p<0.05). At the radius, median trabecular number was lower and trabecular separation was higher in atypical anorexia nervosa than healthy controls (p≤0.04), but there was no difference in failure load between the groups. After controlling for baseline BMI, differences at the radius but not tibia remained significant. At the tibia and radius, median total vBMD, cortical vBMD, and cortical thickness were lower in atypical anorexia nervosa subjects with amenorrhea compared to healthy controls and to atypical anorexia nervosa subjects with eumenorrhea (p≤0.04).
Conclusions: We demonstrate that, despite normal weight, women with atypical anorexia nervosa have impaired vBMD, microarchitecture, and estimated strength compared to healthy controls, with differences more pronounced at the weight-bearing tibia vs non-weight-bearing radius. Individuals with amenorrhea had additional impairments in the non-weight-bearing radius, suggesting an effect of systemic estrogen deficiency. Our data suggest that current normal weight is not protective against impaired bone structure and strength in atypical anorexia nervosa.

Impairments in volumetric bone mineral density, bone microarchitecture, and estimated strength in women with atypical anorexia nervosa

Introduction: Hypercalciuria is one of the reported complications in patients with primary hyperparathyroidism (PHPT). Profound hypercalciuria in the settings of renal stones is considered to be one of the indications for parathyroidectomy. However, limited data is available to describe the rate of hypercalciuria resolution following successful parathyroidectomy in patients with PHPT who had elevated pre-op 24 hour urine calcium levels.
Objective: To describe efficacy of successful parathyroidectomy (defined as normalization of serum calcium) in patients with primary hyperparathyroidism and hypercalciuria (defined as 24 hour urine calcium > 250 mg/24 hr) on resolution of hypercalciuria (defined as 24 hour urine calcium < 200 mg/24hr).
Design: This is a retrospective study in which 51 eligible patients (with parathyroidectomies performed from August 2015 to June 2021) were chart reviewed. Twenty nine patients with complete records pre and post parathyroidectomy were included in the analysis.
Setting: Single outpatient endocrinology center in Las Vegas, Nevada.
Participants: A population of 29 adults aged 29 to 72 years with confirmed primary hyperparathyroidism and hypercalciuria who had a complete resolution of hypercalcemia status post parathyroidectomy.
Main outcome measure: Resolution of hypercalciuria.
Results: 12 patients (41%) had complete resolution of  hypercalciuria after parathyroidectomy. The mean age among patients with resolution was 61.4 years (SD 6.7 years) at the time of surgery vs. 50.5 (SD 11.9 years) among not responders (p= 0.008). There was no significant difference between the resolved and not resolved groups with regard to sex, history of renal stones, history of osteoporosis, location of parathyroid adenoma, pre-op PTH, calcium, and 24 hour urine calcium (p >0.05). Nephrolithiasis occured in 34% of cases. Osteoporosis occurred in 24% of cases. Average pre-op 24 hour urine calcium was 427 mg/24hr (SD  134 mg/24hr, collected on average at 5 months pre-op). Average post-op 24 hour urine calcium was 204 mg/24hr  (SD 83 mg/24hr, collected on average at 22 months post-op).
In a multivariate analysis, for each year of age (at the time of surgery) increase, the odds of resolution of hypercalciuria increased by 37% (p= 0.036, 95% CI [1.020-1.840];  stepwise logistic regression). For each 1 mg increase in pre-op urine calcium odds of resolution of hypercalciuria decreased by 1.7% after successful parathyroidectomy (p=0.033, 95% CI [0.967, 0.999]).
Conclusions: These results suggest that hypercalciuria is less likely to resolve in younger patients with PHPT after successful parathyroidectomy compared to older adults. Our data also suggests that resolution of hypercalciuria in primary hypercalciuria is inversely related to the pre-op 24 hour urine calcium levels (the higher the pre-op 24 hour urine calcium level, the less likely the hypercalciuria to resolve after successful parathyroidectomy).

Hypercalciuria in Young Adults With Primary Hyperparathyroidism Is Less Likely to Resolve After a Successful Parathyroidectomy Compare to Older Adults

Pancreatic ductal adenocarcinoma (PDAC) comprises more than 90% of pancreatic cancer cases and commonly harbors mutations in KRAS and TP53. PDAC is the third leading cause of cancer-related deaths in the US with approximately 10% 5-year relative survival rate. The poor survival rate largely pertains to aggressive growth following metastasis and limited understanding of prognostic factors. Accumulated evidence indicates that PDAC survival rates are inversely correlated with the pancreatic gene expression of INHBA, which encodes inhibin βA, and circulating levels of activin A (a dimer of inhibin βA), which is overexpressed in pancreatic cancer cells. However, potential mechanisms supporting the correlations have remained unclear. PDAC is etiologically related to sustained metaplasia of acinar cells to ductal-like cells (ADM). Therefore, in this study, we tested the hypothesis that activin A plays a tumor-promoting role via ADM. We implanted mouse PDAC KPC (KrasG12D and Tp53R172H) cells into the pancreata of C57BL/6 male mice and divided them into four groups; sham and three groups of orthotopic mice intraperitoneally (IP) injected with either no (TO), scramble (sc) or inhba siRNA (inhba) packaged with CPX nanoparticles, which previously exhibited tumor-targeted delivery, starting on postoperative day 4. On day 16, blood and tissues were harvested for analyses of tumor-related prognostic blood markers and tumor histology. Implanted KPC cells significantly elevated serum activin A levels and induced tumors as demonstrated by the accumulation of SOX9-positive ADM and a-SMA-positive fibroblasts when compared to sham group. Also, metastases occurred to the liver, spleen, kidney, and intestine. No differences were observed between TO and sc groups. However, when compared to sc group, inhba group had significantly suppressed serum activin A levels and reduced tumor size. Statistically, inhba group had fewer metastases and longer survival rates. Histologically, inhba group exhibited more amylase-positive acini conserved and less accumulation of a-SMA-positive cells in the pancreas. Further, the expression of activin A receptor type 2B (ACVR2B) was greatly induced on the acinar cells undergoing ADM transition in sc group, whereas such expression was subdued in inhba group. Collectively, our data indicate that inhba suppression impedes ADM mediated by KPC cells in mice and suggests activin A as one of tumor-initiating factors. It warrants further investigations in human PDAC models and clinical settings to test the potential therapeutic roles of targeting tumor INHBA in early PDAC development.

Potential Role of Activin A During Pancreatic Acinar-to-Ductal Metaplasia of Orthotopic Pancreatic Tumor Mice

Lymphangioleiomyomatosis (LAM) is an estrogen-sensitive lung disease found almost exclusively in women. LAM is characterized by the hyperproliferation of smooth muscle cells creating small tumors throughout the lungs, resulting in the formation of large cysts that replace normal alveolar space. Growth of these tumors and progression of cyst development leads to loss of pulmonary function, and sometimes subsequent lung transplantation. LAM tumor cells contain mutations in one of the tuberous sclerosis genes (TSC1 or TSC2), leading to constitutive activation of the mTORC1 pathway. In fact, mTOR inhibitors are commonly used to treat LAM; however, these drugs are not always effective and have significant side effects, suggesting the need for new therapeutic targets. Additionally, tumors recur even after lung transplantation and LAM cells are found in circulating body fluids, suggesting a metastatic nature of LAM, and a question of the origin of the LAM cell. Due to LAM's estrogen sensitivity, female specificity, and metastatic nature, we previously proposed that LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all of the mice generate uterine tumors characteristic of LAM and half develop lung metastases, suggesting that indeed LAM tumors may be derived from the uterus. Notably, our collaborators recently utilized single cell RNA sequencing with human LAM lung lesions, and found that TSC2-null cells have a strong uterine profile. Using bulk RNASeq analysis of uterine tissue from our mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered increased expression of melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). GPNMB is known to be oncogenic in other cancers and has been shown to be expressed intracellularly in benign cells, but both intracellularly and on the cell surface of tumor cells making GPNMB a good cell surface drug target. This melanocytic marker was not only highly expressed in our mouse model, it was also expressed in TSC2-null cell lines, as well as in human LAM patient lung and uteri samples. Knocking down GPNMB expression by siRNA directed against GPNMB mRNA decreased proliferation, migration, and invasion in TSC2-null cells. We also found that GPNMB's large ectodomain is released from the cell surface of TSC2-null cells and potentially mediated by the protease, Adam10. The ectodomain specifically is implicated in mediating GPNMB's effects on tumor growth. Finally, knocking out GPNMB in TSC2-null cells using CRISPR/Cas9 decreased xenograft tumor growth in mice. Overall, our data thus far demonstrate that GPNMB promotes TSC2-null tumor growth and metastasis. Importantly, the GPNMB ectodomain is a potential biomarker of human LAM, as we detect a significant difference in GPNMB ectodomain levels in patient blood as compared with healthy controls.

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