MMP-13 stimulates osteoclast differentiation and activation in tumour breast bone metastases

INTRODUCTION: The increased bone degradation in osteolytic metastases depends on stimulation of mature osteoclasts and on continuous differentiation of new pre-osteoclasts. Metalloproteinases (MMP)-13 is expressed in a broad range of primary malignant tumours and it is emerging as a novel biomarker. Recent data suggest a direct role of MMP-13 in dissolving bone matrix complementing the activity of MMP-9 and other enzymes. Tumour-microenvironment interactions alter gene expression in malignant breast tumour cells promoting osteolytic bone metastasis. Gene expression profiles revealed that MMP-13 was among the up-regulated genes in tumour-bone interface and its abrogation reduced bone erosion. The precise mechanism remained not fully understood. Our purpose was to further investigate the mechanistic role of MMP-13 in bone osteolytic lesions. METHODS: MDA-MB-231 breast cancer cells that express MMP-13 were used as a model for in vitro and in vivo experiments. Conditioned media from MDA-MB-231 cells were added to peripheral blood mononuclear cultures to monitor pre-osteoclast differentiation and activation. Bone erosion was evaluated after injection of MMP-13-silenced MDA-MB-231 cells into nude mice femurs. RESULTS: MMP-13 was co-expressed by human breast tumour bone metastases with its activator MT1-MMP. MMP-13 was up-regulated in breast cancer cells after in vitro stimulation with IL-8 and was responsible for increased bone resorption and osteoclastogenesis, both of which were reduced by MMP inhibitors. We hypothesized that MMP-13 might be directly involved in the loop promoting pre-osteoclast differentiation and activity. We obtained further evidence for a direct role of MMP-13 in bone metastasis by a silencing approach: conditioned media from MDA-MB-231 after MMP-13 abrogation or co-cultivation of silenced cells with pre-osteoclast were unable to increase pre-osteoclast differentiation and resorption activity. MMP-13 activated pre-MMP-9 and promoted the cleavage of galectin-3, a suppressor of osteoclastogenesis, thus contributing to pre-osteoclast differentiation. Accordingly, MMP-13 abrogation in tumour cells injected into the femurs of nude mice reduced the differentiation of TRAP positive cells in bone marrow and within the tumour mass as well as bone erosion. CONCLUSIONS: These results indicate that within the inflammatory bone microenvironment MMP-13 production was up-regulated in breast tumour cells leading to increased pre-osteoclast differentiation and their subsequent activation

Pathogenetic, clinical and pharmaco-economic assessment in rheumatoid arthritis (RA)

Rheumatoid arthritis (RA) has become one of the most studied autoimmune chronic inflammatory diseases (ACIDs), either from the pathogenetic or from the therapeutic point of view. It is recognized that synovial fibroblasts, TH1 and TH17 cells likely play along with the B cells the most relevant role. The disease has a polygenic background that characterizes the seropositive and the seronegative subsets. Over the years, we realized that no more than 15-20% of long-standing RA (LSRA) treated with conventional drugs can reach full remission, whereas the most recent data in early RA (ERA) have demonstrated that 40-60% can be put into clinical and biological remission. This of course is of crucial importance to avoid any progression of the structural damage that leads to functional disability. If we consider that a disability index score (Health Assessment Questionnaire 0-3) of a severe arthritis can cost up to 21,000 EUs, while a mild disease will cost not more than 5,500 EUs per year, it appears very clear that a low disease activity (LDA) or a remission state (Rem) should be the aim in each single patient, in order to keep the workability and maintain the productivity. This is and should be the major aim in each RA patient

Biochemical Interaction Between Muscle and Bone: A Physiological Reality?

In elderly with a sedentary lifestyle, often suffering from sarcopenia to osteopenia, a training intervention could be an effective countermeasure for bone as well as muscle. Both bone and muscle adapt their mass and strength in response to mechanical loading in part via similar signaling pathways. Bone as well as muscle produces a wide variety of growth factors and cytokines in response to mechanical loading, which are important for their adaptations. It has been hypothesized that in addition to mechanical stimuli, muscle and bone communicate by these factors. Whether such biochemical interaction between both tissues is physiological is a still subject of debate. Here, we provide an overview of a range of biological factors possibly involved in the biochemical cross talk between bone and muscle. In addition, we discuss the plausibility that such interactions are involved in non-pathological adaptation of both tissues, either in paracrine or in endocrine fashion. As yet, convincing experimental evidence for biochemical cross talk between muscle and bone is very limited. Several studies have shown that muscle-derived factors are involved in bone fracture healing as well as in bone adaptation in case of muscle pathology. For involvement of cross talk between muscle and bone in physiological adaptation, there is no definite proof yet. Detailed knowledge of the biochemical interactions between muscle and bone is of clinical importance. It can help to discover pharmacological treatment to be used alone or in parallel with exercise training, thereby reducing the need for high-impact exercise. © 2014 Springer Science+Business Media New York