Isabella Gigante

Periodontal disease: linking the primary inflammation to bone loss.

Periodontal disease (PD), or periodontitis, is defined as a bacterially induced disease of the tooth-supporting (periodontal) tissues. It is characterized by inflammation and bone loss; therefore understanding how they are linked would help to address the most efficacious therapeutic approach. Bacterial infection is the primary etiology but is not sufficient to induce the disease initiation or progression. Indeed, bacteria-derived factors stimulate a local inflammatory reaction and activation of the innate immune system. The innate response involves the recognition of microbial components by host cells, and this event is mediated by toll-like receptors (TLRs) expressed by resident cells and leukocytes. Activation of these cells leads to the release of proinflammatory cytokines and recruitment of phagocytes and lymphocytes. Activation of T and B cells initiates the adaptive immunity with Th1 Th2 Th17 Treg response and antibodies production respectively. In this inflammatory scenario, cytokines involved in bone regulation and maintenance have considerable relevance because tissue destruction is believed to be the consequence of host inflammatory response to the bacterial challenge. In the present review, we summarize host factors including cell populations, cytokines, and mechanisms involved in the destruction of the supporting tissues of the tooth and discuss treatment perspectives based on this knowledge.

Implications of the lysophosphatidic acid signaling axis in liver cancer

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in western countries. The major risk factors for HCC are hepatitis C or B viruses, alcohol and metabolic disorders. The increasing risk of HCC in patients with metabolic disorders (i.e. obesity, diabetes and non-alcoholic steatohepatitis/NASH) regardless of the presence of liver cirrhosis is becoming relevant. Nevertheless, molecular mechanisms linking these risk factors to liver oncogenesis are unclear. This review focuses on the pathogenic role of the lysophosphatidic acid (LPA) pathway in HCC, highlighting the implications of this bioactive phospholipid in liver cancer biology and metabolism and as potential therapeutic target.

Impairment of Bone Remodeling in LIGHT/TNFSF14-Deficient Mice: IMPAIRMENT OF BONE REMODELING IN LIGHT/TNFSF14-DEFICIENT MICE

Multiple cytokines produced by immune cells induce remodeling and aid in maintaining bone homeostasis through differentiation of bone‐forming osteoblasts and bone‐resorbing osteoclasts. Here, we investigate bone remodeling controlled by the tumor necrosis factor (TNF) superfamily cytokine LIGHT. LIGHT‐deficient mice (Tnfsf14‐/‐) exhibit spine deformity and reduced femoral cancellous bone mass associated with an increase in the osteoclast number and a slight decrease of osteoblasts compared with WT mice. The effect of LIGHT in bone cells can be direct or indirect, mediated by both the low expression of the anti‐osteoclastogenic osteoprotegerin (OPG) in B and T cells and reduced levels of the pro‐osteoblastogenic Wnt10b in CD8+ T cells in Tnfsf14‐/‐mice. LIGHT stimulation increases OPG levels in B, CD8+ T, and osteoblastic cells, as well as Wnt10b expression in CD8+ T cells. The high bone mass in Light and T‐ and B‐cell‐deficient mice (Rag‐/Tnfsf14‐) supports the cooperative role of the immune system in bone homeostasis. These results implicate LIGHT as a potential target in bone disease.

Human Myeloma Cell Lines Induce Osteoblast Downregulation of CD99 Which Is Involved in Osteoblast Formation and Activity

CD99 is a transmembrane glycoprotein expressed in physiological conditions by cells of different tissues, including osteoblasts (OBs). High or low CD99 levels have been detected in various pathological conditions, and the supernatant of some carcinoma cell lines can modulate CD99 expression in OB-like cells. In the present work we demonstrate for the first time that two different human myeloma cell lines (H929 and U266) and, in a less degree, their conditioned media significantly downregulate CD99 expression in normal human OBs during the differentiation process. In the same experimental conditions the OBs display a less differentiated phenotype as demonstrated by the decreased expression of RUNX2 and Collagen I. On the contrary, when CD99 was activated by using a specific agonist antibody, the OBs become more active as demonstrated by the upregulation of Alkaline Phosphatase, Collagen I, RUNX2, and JUND expression. Furthermore, we demonstrate that the activation of CD99 is able to induce the phosphorylation of ERK 1/2 and AKT intracellular signal transduction molecules in the OBs.

LIGHT/TNFSF14 affects basal bone remodeling

LIGHT (TNFSF14), expressed by different cells of the immune system, binds two trans-membrane receptors: HVEM and LTβR. It is over-expressed in erosive rheumatoid arthritis and lytic myeloma-bone disease and controversial data have been published on its role in osteoclast (OC) formation in vitro. Here, we investigated the role of LIGHT on in vitro murine osteoclastogenesis model and bone phenotype in LIGHT-/- mice. Firstly, we showed that murine macrophages stimulated with LIGHT alone did not differentiate into OCs. Interestingly, the presence of LIGHT and sub-optimal RANKL concentration displayed synergic effects on OC formation through the early and sustained activation of Akt, NFκB and JNK pathways. Secondly, by microCT we found that the femurs of LIGHT-KO mice exhibited a 30% (p<0.01) decrease in trabecular BV/TV due to a significant reduction in trabecular thickness and number as well as the increase in trabecular spaces respect to wild-type (WT) mice. Furthermore, a five fold increase of OC number/bone surface was found in femora from KO mice compared to WT (p<0.008). To investigate the possible molecular mechanism/s responsible for this bone phenotype in LIGHT-/- mice we studied OPG levels in whole bone marrow (BM) extracts from the femurs of these mice and demonstrated a significant reduction in OPG mRNA transcript respect to WT. Further investigations showed that BM CD8+ T cells and B cell subpopulations from KO mice expressed lower levels of OPG compared to those from WT mice. Consistently, LIGHT treatment in a dose dependent manner increase OPG expression in BM CD8+ T cells and B-cells. In conclusion, our results identified LIGHT as a new important regulator of bone remodeling and highlighted a new modulator of OPG expression.

Shedding LIGHT on bone cell differentiation and Multiple Myeloma-bone disease

1 Department of Basic and Medical Sciences, Neurosciences and Sense Organs, section of Human Anatomy and Histology, University of Bari, 70124 Bari, Italy 2 Department of Clinical and Experimental Medicine, University of Foggia, 70100 Foggia, Italy 3 Department of Emergency and Organ Transplantation, Section of Hematology with Transplantation, University of Bari, Bari, Italy 4 Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy