Endocrinology
Abstract
Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.
Authors
Meredith D. Hartley, Tania Banerji, Ian J. Tagge, Lisa L. Kirkemo, Priya Chaudhary, Evan Calkins, Danielle Galipeau, Mitra D. Shokat, Margaret J. DeBell, Shelby Van Leuven, Hannah Miller, Gail Marracci, Edvinas Pocius, Tapasree Banerji, Skylar J. Ferrara, J. Matthew Meinig, Ben Emery, Dennis Bourdette, Thomas S. Scanlan
Abstract
Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing to bone strength. We evaluated 6 families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. In all the families, we identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane–resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant, c.148C>T (p.Arg50*), whereas the other families had a missense variant, c.185T>G (p.Ile62Ser) or c.191T>G (p.Met64Arg). Subjects with p.Arg50* presented with childhood-onset osteoporosis with or without cranial sclerosis. Patients with p.Ile62Ser or p.Met64Arg had a more severe presentation, with neonatal fractures, severe short stature, and spondylometaphyseal dysplasia. Several subjects had experienced peripheral facial nerve palsy or other neurological manifestations. Bone biopsies showed markedly altered bone material characteristics, including defective bone mineralization. Osteoclast formation and function in vitro was normal. While the p.Arg50* mutation yielded a catalytically inactive enzyme, p.Ile62Ser and p.Met64Arg each enhanced the rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum. SGMS2 pathogenic variants underlie a spectrum of skeletal conditions, ranging from isolated osteoporosis to complex skeletal dysplasia, suggesting a critical role for plasma membrane–bound sphingomyelin metabolism in skeletal homeostasis.
Authors
Minna Pekkinen, Paulien A. Terhal, Lorenzo D. Botto, Petra Henning, Riikka E. Mäkitie, Paul Roschger, Amrita Jain, Matthijs Kol, Matti A. Kjellberg, Eleftherios P. Paschalis, Koen van Gassen, Mary Murray, Pinar Bayrak-Toydemir, Maria K. Magnusson, Judith Jans, Mehran Kausar, John C. Carey, Pentti Somerharju, Ulf H. Lerner, Vesa M. Olkkonen, Klaus Klaushofer, Joost C.M. Holthuis, Outi Mäkitie
Abstract
We have previously reported that the carboxy-terminal proteolytic cleavage product of the COL6α3 chain that we refer to as “endotrophin” has potent effects on transformed mammary ductal epithelial cells in rodents. Endotrophin (ETP) is abundantly expressed in adipose tissue. It is a chemoattractant for macrophages, exerts effects on endothelial cells and through epithelial-mesenchymal transition (EMT) enhances progression of tumor cells. In a recombinant form, human endotrophin exerts similar effects on human macrophages and endothelial cells as its rodent counterpart. It enhances EMT in human breast cancer cells and upon overexpression in tumor cells, the cells become chemoresistant. Here, we report the identification of endotrophin from human plasma. It is circulating at higher levels in breast cancer patients. We have developed neutralizing monoclonal antibodies against human endotrophin and provide evidence for the effectiveness of these antibodies to curb tumor growth and enhance chemosensitivity in a nude mouse model carrying human tumor cell lesions. Combined, the data validate endotrophin as a viable target for anti-tumor therapy for human breast cancer and opens the possibility for further use of these new reagents for anti-fibrotic approaches in liver, kidney, bone marrow and adipose tissue.
Authors
Dawei Bu, Clair Crewe, Christine M. Kusminski, Ruth Gordillo, Alexandra L. Ghaben, Min Kim, Jiyoung Park, Hui Deng, Wei Xiong, Xiao-Zheng Liu, Per Eystein Lønning, Nils Halberg, Adan Rios, Yujun Chang, Anneliese Gonzalez, Ningyan Zhang, Zhiqiang An, Philipp E. Scherer
Abstract
Peripheral hyperinsulinemia resulting from subcutaneous insulin injection is associated with metabolic defects which include abnormal glucose metabolism. The first aim of this study was to quantify the impairments in liver and muscle glucose metabolism that occur when insulin is delivered via a peripheral vein compared to when it is given through its endogenous secretory route (the hepatic portal vein) in overnight fasted conscious dogs. The second aim was to determine if peripheral delivery of a hepato-preferential insulin analog could restore the physiologic response to insulin that occurs under meal feeding conditions. This study is the first to show that hepatic glucose uptake correlates with insulin’s direct effects on the liver under hyperinsulinemic-hyperglycemic conditions. In addition, glucose uptake was equally divided between the liver and muscle when insulin was infused into the portal vein, but when it was delivered into a peripheral vein the percentage of glucose taken up by muscle was 4-times greater than that going to the liver, with liver glucose uptake being less than half of normal. These defects could not be corrected by adjusting the dose of peripheral insulin. On the other hand, hepatic and non-hepatic glucose metabolism could be fully normalized by a hepato-preferential insulin analog.
Authors
Dale S. Edgerton, Melanie Scott, Ben Farmer, Phillip E. Williams, Peter Madsen, Thomas Kjeldsen, Christian L. Brand, Christian Fledelius, Erica Nishimura, Alan D. Cherrington
Abstract
GPR55, a lipid-sensing receptor, is implicated in cell cycle control, malignant cell mobilization, and tissue invasion in cancer. However, a physiological role for GPR55 is virtually unknown for any tissue type. Here, we localize GPR55 to self-renewing ductal epithelial cells and their terminally differentiated progeny in both human and mouse salivary glands. Moreover, we find GPR55 expression downregulated in salivary gland mucoepidermoid carcinomas and GPR55 reinstatement by antitumor irradiation, suggesting that GPR55 controls renegade proliferation. Indeed, GPR55 antagonism increases cell proliferation and function determination in quasiphysiological systems. In addition, Gpr55–/– mice present ~50% enlarged submandibular glands with many more granulated ducts, as well as disordered endoplasmic reticuli and with glycoprotein content. Next, we hypothesized that GPR55 could also modulate salivation and glycoprotein content by entraining differentiated excretory progeny. Accordingly, GPR55 activation facilitated glycoprotein release by itself, inducing low-amplitude Ca2+ oscillations, as well as enhancing acetylcholine-induced Ca2+ responses. Topical application of GPR55 agonists, which are ineffective in Gpr55–/– mice, into adult rodent submandibular glands increased salivation and saliva glycoprotein content. Overall, we propose that GPR55 signaling in epithelial cells ensures both the life-long renewal of ductal cells and the continuous availability of saliva and glycoproteins for oral health and food intake.
Authors
Solomiia Korchynska, Mirjam I. Lutz, Erzsébet Borók, Johannes Pammer, Valentina Cinquina, Nataliya Fedirko, Andrew J. Irving, Ken Mackie, Tibor Harkany, Erik Keimpema
Abstract
The phosphaturic hormone FGF23 is elevated in chronic kidney disease (CKD). The risk of premature death is substantially higher in the CKD patient population, with cardiovascular disease (CVD) as the leading mortality cause at all stages of CKD. Elevated FGF23 in CKD has been associated with increased odds for all-cause mortality; however, whether FGF23 is associated with positive adaptation in CKD is unknown. To test the role of FGF23 in CKD phenotypes, a late osteoblast/osteocyte conditional flox-Fgf23 mouse (Fgf23fl/fl/Dmp1-Cre+/–) was placed on an adenine-containing diet to induce CKD. Serum analysis showed casein-fed Cre+ mice had significantly higher serum phosphate and blood urea nitrogen (BUN) versus casein diet and Cre– genotype controls. Adenine significantly induced serum intact FGF23 in the Cre– mice over casein-fed mice, whereas Cre+ mice on adenine had 90% reduction in serum intact FGF23 and C-terminal FGF23 as well as bone Fgf23 mRNA. Parathyroid hormone was significantly elevated in mice fed adenine diet regardless of genotype, which significantly enhanced midshaft cortical porosity. Echocardiographs of the adenine-fed Cre+ hearts revealed profound aortic calcification and cardiac hypertrophy versus diet and genotype controls. Thus, these studies demonstrate that increased bone FGF23, although associated with poor outcomes in CKD, is necessary to protect against the cardio-renal consequences of elevated tissue phosphate.
Authors
Erica L. Clinkenbeard, Megan L. Noonan, Joseph C. Thomas, Pu Ni, Julia M. Hum, Mohammad Aref, Elizabeth A. Swallow, Sharon M. Moe, Matthew R. Allen, Kenneth E. White
Abstract
Bariatric surgeries including vertical sleeve gastrectomy (VSG) ameliorate obesity and diabetes. Weight-loss and accompanying increases to insulin sensitivity contribute to improved glycemia after surgery, however, studies in humans also suggest weight-independent actions of bariatric procedures to lower blood glucose, possibly by improving insulin secretion. To evaluate this hypothesis, we compared VSG operated mice with pair-fed, sham-surgical controls (PF-Sham) 2 weeks after surgery. This paradigm yielded similar post-operative body weight and insulin sensitivity between VSG and calorically restricted PF-Sham animals. However, VSG improved glucose tolerance and markedly enhanced insulin secretion during oral nutrient and intraperitoneal glucose challenges compared to controls. Islets from VSG mice displayed a unique transcriptional signature enriched for genes involved in Ca2+ signaling and insulin secretion pathways. This finding suggests that bariatric surgery leads to intrinsic changes within the islet that alter function. Indeed, islets isolated from VSG mice had increased glucose-stimulated insulin secretion and a left-shifted glucose sensitivity curve compared to islets from PF-Sham mice. Isolated islets from VSG animals showed corresponding increases in the pulse duration of glucose-stimulated Ca2+ oscillations. Together these findings demonstrate a weight-independent improvement in glycemic control following VSG, which is, in part, driven by improved insulin secretion and associated with substantial changes in islet gene expression. These results support a model in which β-cells play a key role in the adaptation to bariatric surgery and the improved glucose tolerance that is typical of these procedures.
Authors
Jonathan D. Douros, Jingjing Niu, Sophia M. Sdao, Trillian Gregg, Kelsey H. Fisher-Wellman, Manish S. Bharadwaj, Anthony Molina, Ramamani Arumugam, Mackenzie D. Martin, Enrico Petretto, Matthew J. Merrins, Mark A. Herman, Jenny Tong, Jonathan E. Campbell, David D'Alessio
Abstract
Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison to sex-, body mass index- and age-matched control groups with either simple obesity and PCOS, i.e. obesity and androgen excess. IIH women showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone, and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line testosterone significantly enhanced the activity of Na+/K+ ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.
Authors
Michael W. O'Reilly, Connar S.J. Westgate, Catherine Hornby, Hannah Botfield, Angela E. Taylor, Keira Markey, James L. Mitchell, William J. Scotton, Susan P. Mollan, Andreas Yiangou, Carl Jenkinson, Lorna C. Gilligan, Mark Sherlock, James Gibney, Jeremy W. Tomlinson, Gareth G. Lavery, David J. Hodson, Wiebke Arlt, Alexandra J. Sinclair
Abstract
BACKGROUND. Multiple therapeutic strategies to restore immune regulation and slow type 1 diabetes (T1D) progression are in development and testing. A major challenge has been defining biomarkers to prospectively identify subjects likely to benefit from immunotherapy and/or measure intervention effects. We previously found that compared to healthy controls, Tregs from children with new-onset T1D have an altered Treg gene signature (TGS), suggesting this could be an immunoregulatory biomarker. METHODS. nanoString was used to assess the TGS in sorted Tregs (CD4+CD25hiCD127lo) or Peripheral Blood Mononuclear Cells (PBMC) from individuals with T1D or type 2 diabetes, healthy controls, or T1D recipients of immunotherapy. Biomarker discovery pipelines were developed and applied to various sample group comparisons. RESULTS. Compared to controls, the TGS in isolated Tregs or PBMCs is altered in adult new-onset and cross-sectional T1D cohorts, with sensitivity and specificity of biomarkers increased by including T1D-associated single nucleotide polymorphisms in algorithms. The TGS was distinct in T1D versus type 2 diabetes, indicating disease-specific alterations. TGS measurement at the time of T1D onset revealed an algorithm that accurately predicted future rapid versus slow C-peptide decline, as determined by longitudinal analysis of placebo arms of START and T1DAL trials. The same algorithm stratified participants in a phase I/II clinical trial of ustekinumab (αIL-12/23p40) for future rapid versus slow C-peptide decline. CONCLUSION. These data suggest that biomarkers based on measuring Treg gene signatures could be a new approach to stratify patients and monitor autoimmune activity in T1D.
Authors
Anne M. Pesenacker, Virginia Chen, Jana Gillies, Cate Speake, Ashish K. Marwaha, Annika C. Sun, Samuel Chow, Rusung Tan, Thomas Elliott, Jan P. Dutz, Scott J. Tebbutt, Megan K. Levings
Abstract
Growth hormone (GH) decreases with age, and GH therapy has been advocated by some to sustain lean muscle mass and vigor in aging patients and advocated by athletes to enhance performance. Environmental insults and aging lead to DNA damage, which — if unrepaired — results in chromosomal instability and tumorigenesis. We show that GH suppresses epithelial DNA damage repair and blocks ataxia telangiectasia mutated (ATM) kinase autophosphorylation with decreased activity. Decreased phosphorylation of ATM target proteins p53, checkpoint kinase 2 (Chk2), and histone 2A variant led to decreased DNA repair by nonhomologous end-joining. In vivo, prolonged high GH levels resulted in a 60% increase in unrepaired colon epithelial DNA damage. GH suppression of ATM was mediated by induced tripartite motif containing protein 29 (TRIM29) and attenuated tat interacting protein 60 kDa (Tip60). By contrast, DNA repair was increased in human nontumorous colon cells (hNCC) where GH receptor (GHR) was stably suppressed and in colon tissue derived from GHR–/– mice. hNCC treated with etoposide and GH showed enhanced transformation, as evidenced by increased growth in soft agar. In mice bearing human colon GH-secreting xenografts, metastatic lesions were increased. The results elucidate a mechanism underlying GH-activated epithelial cell transformation and highlight an adverse risk for inappropriate adult GH treatment.
Authors
Vera Chesnokova, Svetlana Zonis, Robert Barrett, Hiraku Kameda, Kolja Wawrowsky, Anat Ben-Shlomo, Masaaki Yamamoto, John Gleeson, Catherine Bresee, Vera Gorbunova, Shlomo Melmed
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