Molecular biology of bone remodelling

Bone remodelling is an active and dynamic process that relies on the correct balance between bone resorption by osteoclasts and bone deposition by osteoblasts. Moreover, these two functions must be tightly coupled not only quantitatively, but also in time and space. When the coupling is lost, the correct bone mass could be compromised, leading to several skeletal pathologies. Indeed, bone loss and osteoporosis are the result of an increased osteoclast function and/or a reduced osteoblast activity. In contrast, other pathologies are related to osteoclast failure to resorbe bone, such as osteopetrosis, a rare genetic disorder characterized by an increased bone mass and also linked to an impairment of bone marrow functions. Starting from these assumptions, it is necessary to more deeply understand the molecular mechanisms regulating bone cell functions. Indeed, recent studies evidenced a complex interplay between the immune and skeletal systems, which share several regulatory molecules including cytokines, receptors and transcription factors. These data allowed to more deeply understand the mechanisms underlying bone mass regulation and could open new avenue to identify target molecules for alterantive therapies more efficacious against bone diseases

Updates on Osteoimmunology: What's New on the Cross-Talk Between Bone and Immune System

The term osteoimmunology was coined many years ago to describe the research field that deals with the cross-regulation between bone cells and the immune system. As a matter of fact, many factors that are classically considered immune-related, such as InterLeukins (i.e., IL-6, -11, -17, and -23), Tumor Necrosis Factor (TNF)-α, Receptor-Activator of Nuclear factor Kappa B (RANK), and its Ligand (RANKL), Nuclear Factor of Activated T-cell, cytoplasmatic-1 (NFATc1), and others have all been found to be crucial in osteoclast and osteoblast biology. Conversely, bone cells, which we used to think would only regulate each other and take care of remodeling bone, actually regulate immune cells, by creating the so-called “endosteal niche.” Both osteoblasts and osteoclasts participate to this niche, either by favoring engraftment, or mobilization of Hematopoietic Stem Cells (HSCs). In this review, we will describe the main milestones at the base of the osteoimmunology and present the key cellular players of the bone-immune system cross-talk, including HSCs, osteoblasts, osteoclasts, bone marrow macrophages, osteomacs, T- and B-lymphocytes, dendritic cells, and neutrophils. We will also briefly describe some pathological conditions in which the bone-immune system cross-talk plays a crucial role, with the final aim to portray the state of the art in the mechanisms regulating the bone-immune system interplay, and some of the latest molecular players in the field. This is important to encourage investigation in this field, to identify new targets in the treatment of bone and immune diseases

OSTEOBLAST-DERIVED EXTRACELLULAR VESICLES AND BONE

Extracellular vesicles (EVs) are newly appreciated regulators of tissue homeostasis and a means of intercellular communication. Reports investigated the role of EVs and their cargoes in cellular regulation and have tried to fine-tune their biotechnological use, but to date very little is known on their function in bone biology. To investigate the relevance of EV-mediated communication between bone cells, we isolated EVs from primary mouse osteoblasts and assessed membrane integrity, size and structure by transmission electron microscopy and fluorescence-activated cell sorting. EVs actively shuttled loaded fluorochromes to osteoblasts, monocytes and endothelial cells. Moreover, osteoblast EVs contained mRNAs shared with donor cells. Osteoblasts are known to regulate osteoclastogenesis, osteoclast survival and function by the pro-osteoclastic cytokine, Rankl. Osteoblast EVs were enriched in Rankl, which increased after PTH treatment. These EVs were biologically active, supporting osteoclast survival. EVs isolated from rankl-/- osteoblasts lost this pro-osteoclastic function, indicating its Rankl-dependence. They integrated ex-vivo into murine calvariae, and EV-shuttled fluorochromes were quickly uptaken by the bone upon in vivo EV systemic administration. Rankl-/- mice lack the osteoclast lineage and are negative for its specific marker TRAcP. Treatment of rankl-/- mice with wildtype osteoblast EVs induced the appearance of TRAcP-positive cells in an EV density-dependent manner. Finally, osteoblast EVs internalized and shuttled anti-osteoclast drugs (zoledronate and dasatinib), inhibiting osteoclast activity in vitro and in vivo. We conclude that osteoblast EVs are involved in intercellular communication between bone cells, contribute to the Rankl pro-osteoclastic effect and shuttle anti-osteoclast drugs, representing a potential means of targeted therapeutic delivery. This article is protected by copyright. All rights reserve

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

Interleukin-6 (IL-6) and c-Src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-Src stimulates IL-6 expression through the STAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-Src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-Src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-Src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions

Desafíos y oportunidades de la comunicación científica en Turismo

Conversatorio con revistas especializadas de argentina: Realidad, Tendencias y Desafíos en Turismo - CONDET; Aportes y Transferencias - UNMDP; AYANA. Revista de Investigación en Turismo - IIT-UNLP; MEROPE - CETRIP-UNComahue.Fil: Corbo, Yanina A. Universidad Nacional de Mar del Plata. Facultad de Ciencias Económicas y Sociales; Argentina.Fil: Roldán, Nadia G. Universidad Nacional de Mar del Plata. Facultad de Ciencias Económicas y Sociales; Argentina.Fil: Rucci, Ana Clara. Universidad Nacional de La Plata. Facultad de Ciencias Económicas; Argentina.Fil: Marenzana, Natalia. Universidad Nacional del Comahue. Facultad de Turismo; Argentina

The glycosaminoglycan-binding domain of PRELP acts as a cell type–specific NF-κB inhibitor that impairs osteoclastogenesis

The PRELP heparin sulfate–binding protein translocates to the nucleus, where it impairs NF-κB transcriptional activity, which in turn regulates bone homeostasis

Osteopenia, decreased bone formation and impaired osteoblast development in Sox4 heterozygous mice

The transcription factor Sox4 is vital for fetal development, as Sox4–/– homozygotes die in utero. Sox4 mRNA is expressed in the early embryonic growth plate and is regulated by parathyroid hormone, but its function in bone modeling/remodeling is unknown. We report that Sox4+/– mice exhibit significantly lower bone mass (by dual-energy X-ray absorptiometry) from an early age, and fail to obtain the peak bone mass of wild-type (WT) animals. Microcomputed tomography (μCT), histomorphometry and biomechanical testing of Sox4+/– bones show reduced trabecular and cortical thickness, growth plate width, ultimate force and stiffness compared with WT. Bone formation rate (BFR) in 3-month-old Sox4+/– mice is 64% lower than in WT. Primary calvarial osteoblasts from Sox4+/– mice demonstrate markedly inhibited proliferation, differentiation and mineralization. In these cultures, osterix (Osx) and osteocalcin (OCN) mRNA expression was reduced, whereas Runx2 mRNA was unaffected. No functional defects were found in osteoclasts. Silencing of Sox4 by siRNA in WT osteoblasts replicated the defects observed in Sox4+/– cells. We demonstrate inhibited formation and altered microarchitecture of bone in Sox4+/– mice versus WT, without apparent defects in bone resorption. Our results implicate the transcription factor Sox4 in regulation of bone formation, by acting upstream of Osx and independent of Runx2

Tumour-Derived Extracellular Vesicles (EVs): A Dangerous “Message in A Bottle” for Bone

Several studies have shown the importance of Extracellular Vesicles (EVs) in the intercellular communication between tumour and resident cells. Through EVs, tumour cells can trigger cell-signalling molecules and shuttle exogenous information to target cells, thus promoting spread of the disease. In fact, many processes are fuelled by EVs, such as tumour invasion and dormancy, drug-resistance, immune-surveillance escape, extravasation, extracellular matrix remodelling and metastasis. A key element is certainly the molecular profile of the shed cargo. Understanding the biochemical basis of EVs would help to predict the ability and propensity of cancer cells to metastasize a specific tissue, with the aim to target the release of EVs and to manipulate their content as a possible therapeutic approach. Moreover, EV profiling could help monitor the progression of cancer, providing a useful tool for more effective therapy. This review will focus on all the EV-mediated mentioned mechanisms in the context of both primary bone cancers and bone metastases