Inhibiting TGF-β1 Signaling Protects Joints
Disruption of transforming growth factor (TGF)-β1 signaling during early development in mice results in osteoarthritis (OA)-like knee joints. Chen et al (Am J Pathol 2015, 185:2875–2885) examined the role of TGF-β1 signaling in development of OA in adult joints. No obvious structural changes were observed after conditional inactivation of the TGF-β1 receptor gene Tgfbr2 in the articular cartilage of adult mouse joints. However, the OA progression was dramatically delayed in Tgfbr2 knockout mice after surgical destabilization of the medial meniscus compared with the sham surgical group. Treatment with the Tgfbr2 inhibitor losartan immediately after surgical destabilization of the medial meniscus in wild-type mice also offered similar protection. Targeting TGF-β1 signaling in mature articular cartilage may aid in management of OA.
Suppressing Vascular and Lymphatic Remodeling in Airway Inflammation
Both angiopoietin-2 and tumor necrosis factor (TNF)-α mediate vascular and lymphatic remodeling, key features of sustained inflammation. Le et al (Am J Pathol 2015, 185:2949–2968) studied the interplay between these factors in a mouse model of sustained inflammation. Mice were infected with Mycoplasma pulmonis, followed by treatment with function-blocking angiopoietin-2 and TNF antibodies, singly or in combination. Although individual blocking reduced vascular and lymphatic remodeling and inflammatory response, coupled blocking completely prevented these changes. Genome-wide expression analysis revealed that dual use of function-blocking antibodies synergistically affected a broad range of genes and signaling pathways involved in inflammatory responses. Concomitant immunoneutralization of angiopoietin-2 and TNF-α may effectively suppress vascular and lymphatic remodeling in sustained airway inflammation.
Microbiota Influences Risk of Celiac Disease
The modulation of gluten-induced immunopathology in celiac disease by the gut microbiota lacks direct evidence. Using complementary strategies in HLA-DQ8–humanized mice, Galipeau et al (Am J Pathol 2015, 185:2969–2982) studied host response to gluten under different microbial conditions. Germ-free, ie clean specific pathogen-free (SPF) mice with microbiota free of opportunistic pathogens and Proteobacteria, showed attenuated response to gluten compared with germ-free and conventional SPF mice. Conventional SPF mice developed more severe gluten-induced pathology compared with clean mice, which was ameliorated by perinatal antibiotic treatment that resulted in Proteobacteria expansion. Supplementation with a specific pathobiont reversed the protective effect of the benign microbiota in clean SPF mice. Therapies targeting microbiota may aid in the management of celiac disease patients with moderate genetic risk.
Linking Cutaneous Pigmentation and Itch
The interaction between cutaneous pigmentation and itch is poorly understood. Shimizu et al (Am J Pathol 2015, 185:3003–3010) investigated whether the stress-response neuropeptide α-melanocyte–stimulating hormone (α-MSH), which can induce cutaneous pigmentation, elicits itch-related responses. Intradermal injection of mice with α-MSH induced scratching at the injected site in a dose-dependent manner, which was inhibited by antagonists of μ-opioid receptor H1 histamine receptor. α-MSH also elicited scratching in mast cell–deficient mice. l-Histidine decarboxylase, which is involved in histamine biosynthesis, was detected in both mast cells and epidermal keratinocytes. α-MSH treatment specifically induced immediate histamine release in the mouse keratinocyte cell line Pam212. α-MSH thus induces itching via histidine, likely from keratinocytes rather than mast cells.
Modeling Progression of Ductal Carcinoma in Situ
Progression of ductal carcinoma in situ (DCIS) has been poorly modeled. Russell et al (Am J Pathol 2015, 185:3076–3089) therefore developed a preclinical mouse model to explore advancement of early-stage DCIS. To avoid surgical confounders, human breast cancer DCIS.com cells were intraductally injected into mouse mammary teats. The DCIS-like lesions in the mammary ducts fully mimicked human DCIS histology, including progression from tumor incorporation, neoplasia, and DCIS to development of invasive cancer. Affected myoepithelium progressively lost early (p63), intermediate (calponin), and late (α-smooth muscle actin) myoepithelial cell differentiation markers. Similar loss was also observed in single time-point biopsy specimens from studied pure DCIS patient samples. Myoepithelial loss of calponin correlated with the gain of basal marker p63 in adjacent tumor cells, suggesting that calponin expression may predict risk of progression to invasive disease.
Published online: September 25, 2015
© 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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- Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ ProgressionThe American Journal of PathologyVol. 185Issue 11
- PreviewWe describe a preclinical model that investigates progression of early-stage ductal carcinoma in situ (DCIS) and report that compromised myoepithelial cell differentiation occurs before transition to invasive disease. Human breast cancer MCF10DCIS.com cells were delivered into the mouse mammary teat by intraductal injection in the absence of surgical manipulations and accompanying wound-healing confounders. DCIS-like lesions developed throughout the mammary ducts with full representation of human DCIS histologic patterns.
- Synergistic Actions of Blocking Angiopoietin-2 and Tumor Necrosis Factor-α in Suppressing Remodeling of Blood Vessels and Lymphatics in Airway InflammationThe American Journal of PathologyVol. 185Issue 11
- PreviewRemodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection.
- Intestinal Microbiota Modulates Gluten-Induced Immunopathology in Humanized MiceThe American Journal of PathologyVol. 185Issue 11
- PreviewCeliac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. The recent increase in CD incidence suggests that additional environmental factors, such as intestinal microbiota alterations, are involved in its pathogenesis. However, there is no direct evidence of modulation of gluten-induced immunopathology by the microbiota. We investigated whether specific microbiota compositions influence immune responses to gluten in mice expressing the human DQ8 gene, which confers moderate CD genetic susceptibility.
- Attenuation of the Progression of Articular Cartilage Degeneration by Inhibition of TGF-β1 Signaling in a Mouse Model of OsteoarthritisThe American Journal of PathologyVol. 185Issue 11
- PreviewTransforming growth factor beta 1 (TGF-β1) is implicated in osteoarthritis. We therefore studied the role of TGF-β1 signaling in the development of osteoarthritis in a developmental stage-dependent manner. Three different mouse models were investigated. First, the Tgf-β receptor II (Tgfbr2) was specifically removed from the mature cartilage of joints. Tgfbr2-deficient mice were grown to 12 months of age and were then euthanized for collection of knee and temporomandibular joints. Second, Tgfbr2-deficient mice were subjected to destabilization of the medial meniscus (DMM) surgery.
- Histamine Released from Epidermal Keratinocytes Plays a Role in α-Melanocyte–Stimulating Hormone-Induced Itching in MiceThe American Journal of PathologyVol. 185Issue 11
- PreviewSunburn, wound repair, and chronic renal failure with hemodialysis are usually accompanied by both pigmentation and itching. Proopiomelanocortin-derived α-melanocyte–stimulating hormone (α-MSH) is produced in response to external stimuli, such as UV irradiation, and is involved in cutaneous pigmentation. However, it is unclear whether α-MSH is also involved in the itching. We therefore investigated whether α-MSH elicited itch-related responses in mice. We found that an intradermal injection of α-MSH induced hind-paw scratching, an itch-related response, in mice.