Kolachala et al. integrated single-cell and spatial transcriptomics to identify cellular networks and coordinated molecules distinguishing active Crohn’s disease and assessed their spatial distribution on diseased tissues. The cover image shows ileal tissue from a patient with Crohn’s disease, revealing CD74 (green) and HLA-DR (red) expression in the epithelial cells. DAPI (nuclear stain) is shown in blue, and E-cadherin (epithelial marker) is shown in white.
Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare, and the persistence of cutaneous disease can prevent complete disease remission. The non-invasive study of cutaneous expression signatures through tape stripping (TS) holds the potential to reveal mechanisms underlying disease heterogeneity and organ-specific inflammation. The objectives of this study were to 1) define TS expression signatures in lesional and non-lesional JDM skin, 2) analyze TS signatures to identify JDM disease endotypes and 3) compare TS and blood signatures. While JDM lesional skin demonstrated interferon signaling as the top upregulated pathway, non-lesional skin uniquely highlighted pathways involved in metabolism, angiogenesis and calcium signaling. Both lesional and non-lesional skin shared inflammasome pathway dysregulation. Using unsupervised clustering of skin expression data, we identified a treatment-refractory JDM subgroup distinguished by upregulation of genes associated with mitochondrial dysfunction. The treatment-refractory JDM subgroup also demonstrated higher interferon, angiogenesis and innate immune expression scores in skin and blood, although scores were more pronounced in skin as compared to blood. Tape-stripping expression signatures in JDM provided insight into disease mechanisms and molecular subgroups. Skin, as compared to blood, transcriptional profiles served as more sensitive markers to classify disease subgroups and identify candidate treatment targets.
Jessica L. Turnier, Sarah M.H. Vandenbergen, Madison E. McClune, Christine Goudsmit, Sophia Matossian, Meredith Riebschleger, Nadine Saad, Jacqueline A. Madison, Smriti Mohan, Johann E. Gudjonsson, Lam C. Tsoi, Celine C. Berthier, J. Michelle Kahlenberg
Septic arthritis, the most severe joint disease, is frequently caused by Staphylococcus aureus (S. aureus). A substantial proportion of patients with septic arthritis experience poor joint outcomes, often necessitating joint replacement surgery. Here, we show that monocyte depletion confers full protection against bone erosion in a septic arthritis mouse model. In the infected synovium, Ly6Chigh monocytes exhibited increased expression of osteoclastogenesis-related molecules, including CCR2, c-Fms, and RANK. S. aureus lipoproteins induced elevated levels of RANKL, MCSF, and CCL-2 in joints, with synovial fibroblasts identified as the major RANKL producer. Anti-RANKL treatment prevented bone destruction in both local and hematogenous septic arthritis murine models. Importantly, combining anti-RANKL treatment with antibiotics provided robust protection against joint damage. Our results indicate that the infiltration and transformation of monocytes into bone-destructive, osteoclast-like cells are key mechanisms in septic arthritis. Combining anti-RANKL and antibiotic therapy represents a promising therapy against this devastating disease.
Zhicheng Hu, Meghshree Deshmukh, Anders Jarneborn, Miriam Bollmann, Carmen Corciulo, Pradeep Kumar Kopparapu, Abukar Ali, Mattias N.D. Svensson, Cecilia Engdahl, Rille Pullerits, Majd Mohammad, Tao Jin
Máté Sándor, Balázs Csaba Németh, Alexandra Demcsák, Miklós Sahin-Tóth
Mutations in the anoctamin5 (ANO5) gene can lead to musculoskeletal disorders, with monoallelic (autosomal dominant) mutations typically presenting as skeletal abnormalities known as Gnathodiaphyseal dysplasia (GDD). Clinically, GDD is characterized by thickened cortices of long bones and mandibles, narrowed medullary cavities, and increased bone fragility. While autophagy is necessary in regulating bone formation, the specific relationship between ANO5 and autophagy remains poorly understood. In this study, we demonstrated that Ano5 deficiency activates autophagy in mouse cranial osteoblasts (mCOBs), leading to enhanced osteogenic capacity in Ano5-/- mCOBs. The application of 3-Methyladenine (3-MA) and chloroquine (CQ) reversed the excessive osteogenesis observed in Ano5-/- mCOBs. Further analysis revealed that Ano5 deficiency upregulates the expression of ATG9A, and silencing ATG9A significantly reduces both autophagy and osteogenic activity in Ano5-/- mCOBs. Additionally, the AMP-activated protein kinase (AMPK) was found to regulate ATG9A positively, and inhibiting AMPK reduced ATG9A expression, which in turn mitigated excessive osteogenesis of Ano5-/- mCOBs. Moreover, in vivo experiments confirmed that treatment with 3-MA alleviates the bone phenotype abnormalities in Ano5-/- mice. These findings suggest that Ano5 negatively regulates autophagy, contributing to illuminate pathogenesis of GDD. Meanwhile, this research highlights potential therapeutic strategies targeting autophagy to pave the way for the clinical manifestations of GDD.
Shuai Zhang, Shengnan Wang, Sirui Liu, Xiu Liu, Mingyue Zhang, Huichong Xu, Xiaoyu Wang, Hongyu Li, Ying Hu
Many risk-eligible women refuse tamoxifen for primary prevention of breast cancer due to concerns about common side effects such as vasomotor symptoms. Tamoxifen may also induce or worsen insulin resistance and hypertriglyceridemia, especially in women with obesity. Bazedoxifene/conjugated estrogens (BZA/CE) reduces vasomotor symptoms and is currently undergoing evaluation for breast cancer risk reduction. However, the impact of BZA/CE on insulin resistance and metabolic health, particularly in those with excess adiposity, is understudied. Here, we examined the effects of obesity on response to BZA/CE in a rat model of breast cancer risk using older ovary-intact rats. Female Wistar rats received carcinogen to increase mammary cancer risk and were fed a high-fat diet to promote obesity. Lean and obese rats were selected based on adiposity, then randomized to BZA/CE or vehicle for 8 weeks. BZA/CE reduced adiposity, enriched small (insulin-sensitive) mammary adipocytes, increased the abundance of beneficial metabolic gut microbes (Faecalbaculum rodentium and Odoribacter laneus), and reversed obesity-associated changes in lipids and adipokines. BZA/CE also reversed obesity-induced mammary enrichment of cell proliferation pathways, consistent with risk-reducing effects. Together, these data support the use of BZA/CE to improve metabolic health and reduce breast cancer risk in individuals with obesity.
Erin D. Giles, Katherine L. Cook, Ramsey M. Jenschke, Karen A. Corleto, Danilo Landrock, Tara N. Mahmood, Katherine E. Sanchez, Alina Levin, Stephen D. Hursting, Bruce F. Kimler, Barry S. Komm, Carol J. Fabian