RESUMEN
The existing suite of therapies for bone diseases largely act to prevent further bone loss but fail to stimulate healthy bone formation and repair. We describe an endogenous osteopeptide (PEPITEM) with anabolic osteogenic activity, regulating bone remodeling in health and disease. PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength. Simultaneously, PEPITEM stimulates an inhibitory paracrine loop: promoting osteoblast release of the decoy receptor osteoprotegerin, which sequesters RANKL, thereby limiting osteoclast activity and bone resorption. In disease models, PEPITEM therapy halts osteoporosis-induced bone loss and arthritis-induced bone damage in mice and stimulates new bone formation in osteoblasts derived from patient samples. Thus, PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss, promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover.
Asunto(s)
Resorción Ósea , Osteoblastos , Osteogénesis , Animales , Humanos , Osteoblastos/metabolismo , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Ratones , Resorción Ósea/patología , Resorción Ósea/metabolismo , Anabolizantes/farmacología , Anabolizantes/uso terapéutico , Remodelación Ósea/efectos de los fármacos , Osteoporosis/patología , Osteoporosis/metabolismo , Osteoporosis/tratamiento farmacológico , Ligando RANK/metabolismo , Osteoclastos/metabolismo , Osteoclastos/efectos de los fármacos , Desarrollo Óseo/efectos de los fármacos , Osteoprotegerina/metabolismo , Femenino , Transducción de Señal/efectos de los fármacos , Péptidos/farmacología , Masculino , Ratones Endogámicos C57BL , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patologíaRESUMEN
To investigate the effect of the therapeutic treatment of the immunopeptide, peptide inhibitor of trans-endothelial migration (PEPITEM) on the severity of disease in a mouse model of experimental autoimmune encephalomyelitis (EAE) as a model for human multiple sclerosis (MS), a series of experiments were conducted. Using C57BL/6 female mice, we dosed the PEPITEM in the EAE model via IP after observing the first sign of inflammation. The disease was induced using MOG35-55 and complete Freund's adjuvants augmented with pertussis toxin. The EAE score was recorded daily until the end of the experiment (21 days). The histological and immunohistochemistry analysis was conducted on the spinal cord sections. A Western blot analysis was performed to measure the protein concentration of MBP, MAP-2, and N-Cadherin, and ELISA kits were used to measure IL-17 and FOXP3 in the serum and spinal cord lysate. The therapeutic treatment with PEPITEM reduced the CNS infiltration of T cells, and decreased levels of the protein concertations of MBP, MAP-2, and N-Cadherin were observed, in addition to reduced concertations of IL-17 and FOXP3. Using PEPITEM alleviated the severity of the symptoms in the EAE model. Our study revealed the potential of PEPITEM to control inflammation in MS patients and to reduce the harmful effects of synthetic drugs.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Humanos , Femenino , Ratones , Animales , Interleucina-17/efectos adversos , Citocinas/metabolismo , Ratones Endogámicos C57BL , Inflamación/tratamiento farmacológico , Inflamación/patología , Médula Espinal/metabolismo , Esclerosis Múltiple/patología , Péptidos , Linfocitos T/metabolismo , Cadherinas , Factores de Transcripción ForkheadRESUMEN
Dysregulation of leukocyte trafficking, lipid metabolism, and other metabolic processes are the hallmarks that underpin and drive pathology in obesity. Current clinical management targets alternations in lifestyle choices (e.g. exercise, weight loss) to limit the impact of the disease. Crucially, re-gaining control over the pathogenic cellular and molecular processes may offer an alternative, complementary strategy for obese patients. Here we investigate the impact of the immunopeptide, PEPITEM, on pancreas homeostasis and leukocyte trafficking in mice on high-fed obesogenic diet (HFD). Both prophylactic and therapeutic treatment with PEPITEM alleviated the effects of HFD on the pancreas, reducing pancreatic beta cell size. Moreover, PEPITEM treatment also limited T-cell trafficking (CD4+ T-cells and KLRG1+ CD3+ T-cells) to obese visceral, but not subcutaneous, adipose tissue. Similarly, PEPITEM treatment reduced macrophage numbers within the peritoneal cavity of mice on HFD diet at both 6 and 12 weeks. By contrast, PEPITEM therapy elevated numbers of T and B cells were observed in the secondary lymphoid tissues (e.g. spleen and inguinal lymph node) when compared to the untreated HFD controls. Collectively our data highlights the potential for PEPITEM as a novel therapy to combat the systemic low-grade inflammation experienced in obesity and minimize the impact of obesity on pancreatic homeostasis. Thus, offering an alternative strategy to reduce the risk of developing obesity-related co-morbidities, such as type 2 diabetes mellitus, in individuals at high risk and struggling to control their weight through lifestyle modifications.
Asunto(s)
Diabetes Mellitus Tipo 2 , Ratones , Animales , Diabetes Mellitus Tipo 2/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/patología , Inflamación/patología , Dieta , Linfocitos T CD4-Positivos/metabolismo , Ratones Endogámicos C57BL , Tejido AdiposoRESUMEN
Leukocyte recruitment is a pivotal process in the regulation and resolution of an inflammatory episode. It is vital for the protective responses to microbial infection and tissue damage, but is the unwanted reaction contributing to pathology in many immune mediated inflammatory diseases (IMIDs). Indeed, it is now recognized that patients with IMIDs have defects in at least one, if not multiple, check-points regulating the entry and exit of leukocytes from the inflamed site. In this review, we will explore our understanding of the imbalance in recruitment that permits the accumulation and persistence of leukocytes in IMIDs. We will highlight old and novel pharmacological tools targeting these processes in an attempt to trigger resolution of the inflammatory response. In this context, we will focus on cytokines, chemokines, known pro-resolving lipid mediators and potential novel lipids (e.g., sphingosine-1-phosphate), along with the actions of glucocorticoids mediated by 11-beta hydroxysteroid dehydrogenase 1 and 2.
RESUMEN
T cell migration across vascular endothelium is essential for T cell responses, as through the expression of specific tissue-homing receptors, these cells then access peripheral tissues, with the goal of eliminating invading pathogens and/or tumor cells. However, aberrant trafficking of T cells to peripheral tissues contributes to the development of most chronic inflammatory diseases. Very little is known about the mechanisms by which T cell trafficking is regulated during inflammation, and it is thus difficult to target this aspect of pathology for the development of new therapies. It is therefore important to understand the pathways involved in regulating the recruitment of immune cells.