1. Investigación

Nowadays, the treatment of musculoskeletal diseases represents a major challenge in the developed world. Diseases such as osteoporosis, osteoarthritis and arthritis have a high incidence and prevalence as a consequence of population aging, and they are also associated with a socioeconomic burden. Many efforts have been made to find a treatment for these diseases with various levels of success, but new approaches are still needed to deal with these pathologies. In this context, one peptide derived for the C-terminal extreme of the Parathormone related Peptide (PTHrP) called Osteostatin can be useful to treat musculoskeletal diseases. This pentapeptide (TRSAW) has demonstrated both in different in vitro and in vivo models, its role as a molecule with anti-resorptive, anabolic, anti-inflammatory, and anti-antioxidant properties. Our aim with this work is to review the Osteostatin main features, the knowledge of its mechanisms of action as well as its possible use for the treatment of osteoporosis, bone regeneration and fractures and against arthritis given its anti-inflammatory properties.

Inflammation is a common factor of pathologies such as obesity, type 2 diabetes or neurodegenerative diseases. Chronic inflammation is considered part of the pathogenic mechanisms of different disorders associated with aging. Interestingly, peripheral inflammation and the associated metabolic alterations not only facilitate insulin resistance and diabetes but also neurodegenerative disorders. Therefore, the identification of novel pathways, common to the development of these diseases, which modulate the immune response and signaling is key. It will provide highly relevant information to advance our knowledge of the multifactorial process of aging, and to establish new biomarkers and/or therapeutic targets to counteract the underlying chronic inflammatory processes. One novel pathway that regulates peripheral and central immune responses is triggered by the cytokines pleiotrophin (PTN) and midkine (MK), which bind its receptor, Receptor Protein Tyrosine Phosphatase (RPTP) b/z, and inactivate its phosphatase activity. In this review, we compile a growing body of knowledge suggesting that PTN and MK modulate the immune response and/or inflammation in different pathologies characterized by peripheral inflammation associated with insulin resistance, such as aging, and in central disorders characterized by overt neuroinflammation, such as neurodegenerative diseases and endotoxemia. Evidence strongly suggests that regulation of the PTN and MK signaling pathways may provide new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN and/or MK cerebral levels and neuroinflammation. Importantly, we discuss existing therapeutics, and others being developed, that modulate these signaling pathways, and their potential use in pathologies characterized by overt neuroinflammation.

The lens proteome undergoes dramatic composition changes during development and maturation. A defective developmental process leads to congenital cataracts that account for about 30% of cases of childhood blindness. Gene mutations are associated with approximately 50% of early-onset forms of lens opacity, with the remainder being of unknown etiology. To gain a better understanding of cataractogenesis, we utilized a transgenic mouse model expressing a mutant ubiquitin protein in the lens (K6W-Ub) that recapitulates most of the early pathological changes seen in human congenital cataracts. We performed mass spectrometry-based tandem-mass-tag quantitative proteomics in E15, P1, and P30 control or K6W-Ub lenses. Our analysis identified targets that are required for early normal differentiation steps and altered in cataractous lenses, particularly metabolic pathways involving glutathione and amino acids. Computational molecular phenotyping revealed that glutathione and taurine were spatially altered in the K6W-Ub cataractous lens. High-performance liquid chromatography revealed that both taurine and the ratio of reduced glutathione to oxidized glutathione, two indicators of redox status, were differentially compromised in lens biology. In sum, our research documents that dynamic proteome changes in a mouse model of congenital cataracts impact redox biology in lens. Our findings shed light on the molecular mechanisms associated with congenital cataracts and point out that unbalanced redox status due to reduced levels of taurine and glutathione, metabolites already linked to age-related cataract, could be a major underlying mechanism behind lens opacities that appear early in life.

Purpose: During lens fiber cell differentiation, organelles are removed in an ordered manner to ensure lens clarity. A critical step in this process is removal of the cell nucleus, but the mechanisms by which this occurs are unclear. In this study, we investigate the role of a cyclin-dependent kinase 1 (CDK1) regulatory loop in controlling lens fiber cell denucleation (LFCD). Methods: We examined lens differentiation histologically in two different vertebrate models. An embryonic chick lens culture system was used to test the role of CDK1, cell division cycle 25 (CDC25), WEE1, and PP2A in LFCD. Additionally, we used three mouse models that express high levels of the CDK inhibitor p27 to test whether increased p27 levels affect LFCD. Results: Using chick lens organ cultures, small-molecule inhibitors of CDK1 and CDC25 inhibit LFCD, while inhibiting the CDK1 inhibitory kinase WEE1 potentiates LFCD. Additionally, treatment with an inhibitor of PP2A, which indirectly inhibits CDK1 activity, also increased LFCD. Three different mouse models that express increased levels of p27 through different mechanisms show impaired LFCD. Conclusions: Here we define a conserved nonmitotic role for CDK1 and its upstream regulators in controlling LFCD. We find that CDK1 functionally interacts with WEE1, a nuclear kinase that inhibits CDK1 activity, and CDC25 activating phosphatases in cells where CDK1 activity must be exquisitely regulated to allow for LFCD. We also provide genetic evidence in multiple in vivo models that p27, a CDK1 inhibitor, inhibits lens growth and LFCD.

Inability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule-based minus-end-directed motor proteins, the well-characterized dynein, and the less-studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti-aging purposes.