Role of the osteocyte in bone metastasis - The importance of networking.

Metastatic bone disease is a complex condition resulting from the migration and colonization of cancer cells from their primary site to the bone microenvironment, where they typically develop a metastatic niche. Osteocytes, the most abundant cells in bone tissue and the master regulators of bone remodelling, are increasingly thought to play a crucial role in this process through intricate interactions with cancer cells. This review covers the recent progress made in exploring the multifaceted interactions between osteocytes and cancer cells in the metastatic microenvironment, highlighting the importance of signalling networks in bone metastases. Though these interactions are particularly complex, the renewed focus of researchers on osteocytes within the last 5 years has uncovered multiple new potential molecular mechanisms underlying osteocyte-mediated regulation of cancer cell survival, proliferation, and invasion. A number of key papers will be discussed in detail, emphasizing the significance of signalling pathways and molecular crosstalk, and exploring potential therapeutic strategies targeting osteocyte-cancer cell interactions to improve patient treatment and outcomes

Utilizing 3D Models to Unravel the Dynamics of Myeloma Plasma Cells' Escape from the Bone Marrow Microenvironment.

Recent therapeutic advancements have markedly increased the survival rates of individuals with multiple myeloma (MM), doubling survival compared to pre-2000 estimates. This progress, driven by highly effective novel agents, suggests a growing population of MM survivors exceeding the 10-year mark post-diagnosis. However, contemporary clinical observations indicate potential trends toward more aggressive relapse phenotypes, characterized by extramedullary disease and dominant proliferative clones, despite these highly effective treatments. To build upon these advances, it is crucial to develop models of MM evolution, particularly focusing on understanding the biological mechanisms behind its development outside the bone marrow. This comprehensive understanding is essential to devising innovative treatment strategies. This review emphasizes the role of 3D models, specifically addressing the bone marrow microenvironment and development of extramedullary sites. It explores the current state-of-the-art in MM modelling, highlighting challenges in replicating the disease's complexity. Recognizing the unique demand for accurate models, the discussion underscores the potential impact of these advanced 3D models on understanding and combating this heterogeneous and still incurable disease

Mechanical Stimulation Modulates Osteocyte Regulation of Cancer Cell Phenotype

Breast and prostate cancers preferentially metastasise to bone tissue, with metastatic lesions forming in the skeletons of most patients. On arriving in bone tissue, disseminated tumour cells enter a mechanical microenvironment that is substantially different to that of the primary tumour and is largely regulated by bone cells. Osteocytes, the most ubiquitous bone cell type, orchestrate healthy bone remodelling in response to physical exercise. However, the effects of mechanical loading of osteocytes on cancer cell behaviour is still poorly understood. The aim of this study was to characterise the effects of osteocyte mechanical stimulation on the behaviour of breast and prostate cancer cells. To replicate an osteocyte-controlled environment, this study treated breast (MDA-MB-231 and MCF-7) and prostate (PC-3 and LNCaP) cancer cell lines with conditioned media from MLO-Y4 osteocyte-like cells exposed to mechanical stimulation in the form of fluid shear stress. We found that osteocyte paracrine signalling acted to inhibit metastatic breast and prostate tumour growth, characterised by reduced proliferation and invasion and increased migration. In breast cancer cells, these effects were largely reversed by mechanical stimulation of osteocytes. In contrast, conditioned media from mechanically stimulated osteocytes had no effect on prostate cancer cells. To further investigate these interactions, we developed a microfluidic organ-chip model using the Emulate platform. This new organ-chip model enabled analysis of cancer cell migration, proliferation and invasion in the presence of mechanical stimulation of osteocytes by fluid shear stress, resulting in increased invasion of breast and prostate cancer cells. These findings demonstrate the importance of osteocytes and mechanical loading in regulating cancer cell behaviour and the need to incorporate these factors into predictive in vitro models of bone metastasis

In silico assessment of the bone regeneration potential of complex porous scaffolds.

Mechanical environment plays a crucial role in regulating bone regeneration in bone defects. Assessing the mechanobiological behavior of patient-specific orthopedic scaffolds in-silico could help guide optimal scaffold designs, as well as intra- and post-operative strategies to enhance bone regeneration and improve implant longevity. Additively manufactured porous scaffolds, and specifically triply periodic minimal surfaces (TPMS), have shown promising structural properties to act as bone substitutes, yet their ability to induce mechanobiologially-driven bone regeneration has not been elucidated. The aim of this study is to i) explore the bone regeneration potential of TPMS scaffolds made of different stiffness biocompatible materials, to ii) analyze the influence of pre-seeding the scaffolds and increasing the post-operative resting period, and to iii) assess the influence of patient-specific parameters, such as age and mechanosensitivity, on outcomes. To perform this study, an in silico model of a goat tibia is used. The bone ingrowth within the scaffold pores was simulated with a mechano-driven model of bone regeneration. Results showed that the scaffold's architectural properties affect cellular diffusion and strain distribution, resulting in variations in the regenerated bone volume and distribution. The softer material improved the bone ingrowth. An initial resting period improved the bone ingrowth but not enough to reach the scaffold's core. However, this was achieved with the implantation of a pre-seeded scaffold. Physiological parameters like age and health of the patient also influence the bone regeneration outcome, though to a lesser extent than the scaffold design. This analysis demonstrates the importance of the scaffold's geometry and its material, and highlights the potential of using mechanobiological patient-specific models in the design process for bone substitutes

Altered biomechanical stimulation of the developing hip joint in presence of hip dysplasia risk factors

Fetal kicking and movements generate biomechanical stimulation in the fetal skeleton, which is important for prenatal musculoskeletal development, particularly joint shape. Developmental dysplasia of the hip (DDH) is the most common joint shape abnormality at birth, with many risk factors for the condition being associated with restricted fetal movement. In this study, we investigate the biomechanics of fetal movements in such situations, namely fetal breech position, oligohydramnios and primiparity (firstborn pregnancy). We also investigate twin pregnancies, which are not at greater risk of DDH incidence, despite the more restricted intra-uterine environment. We track fetal movements for each of these situations using cine-MRI technology, quantify the kick and muscle forces, and characterise the resulting stress and strain in the hip joint, testing the hypothesis that altered biomechanical stimuli may explain the link between certain intra-uterine conditions and risk of DDH. Kick force, stress and strain were found to be significantly lower in cases of breech position and oligohydramnios. Similarly, firstborn fetuses were found to generate significantly lower kick forces than non-firstborns. Interestingly, no significant difference was observed in twins compared to singletons. This research represents the first evidence of a link between the biomechanics of fetal movements and the risk of DDH, potentially informing the development of future preventative measures and enhanced diagnosis. Our results emphasise the importance of ultrasound screening for breech position and oligohydramnios, particularly later in pregnancy, and suggest that earlier intervention to correct breech position through external cephalic version could reduce the risk of hip dysplasia

Function and failure of the fetal membrane : modelling the mechanics of the chorion and amnion

The fetal membrane surrounds the fetus during pregnancy and is a thin tissue composed of two layers, the chorion and the amnion. While rupture of this membrane normally occurs at term, preterm rupture can result in increased risk of fetal mortality and morbidity, as well as danger of infection in the mother. Although structural changes have been observed in the membrane in such cases, the mechanical behaviour of the human fetal membrane in vivo remains poorly understood and is challenging to investigate experimentally. Therefore, the objective of this study was to develop simplified finite element models to investigate the mechanical behaviour and rupture of the fetal membrane, particularly its constituent layers, under various physiological conditions. It was found that modelling the chorion and amnion as a single layer predicts remarkably different behaviour compared with a more anatomically-accurate bilayer, significantly underestimating stress in the amnion and under-predicting the risk of membrane rupture. Additionally, reductions in chorion-amnion interface lubrication and chorion thickness (reported in cases of preterm rupture) both resulted in increased membrane stress. Interestingly, the inclusion of a weak zone in the fetal membrane that has been observed to develop overlying the cervix would likely cause it to fail at term, during labour. Finally, these findings support the theory that the amnion is the dominant structural component of the fetal membrane and is required to maintain its integrity. The results provide a novel insight into the mechanical effect of structural changes in the chorion and amnion, in cases of both normal and preterm rupture

Linking the community structure of arbuscular mycorrhizal fungi and plants: a story of interdependence?

Arbuscular mycorrhizal fungi (AMF) are crucial to plants and vice versa, but little is known about the factors linking the community structure of the two groups. We investigated the association between AMF and the plant community structure in the nearest neighborhood of Festuca brevipila in a semiarid grassland with steep environmental gradients, using high-throughput sequencing of the Glomeromycotina (former Glomeromycota). We focused on the Passenger, Driver and Habitat hypotheses: (i) plant communities drive AMF (passenger); (ii) AMF communities drive the plants (driver); (iii) the environment shapes both communities causing covariation. The null hypothesis is that the two assemblages are independent and this study offers a spatially explicit novel test of it in the field at multiple, small scales. The AMF community consisted of 71 operational taxonomic units, the plant community of 47 species. Spatial distance and spatial variation in the environment were the main determinants of the AMF community. The structure of the plant community around the focal plant was a poor predictor of AMF communities, also in terms of phylogenetic community structure. Some evidence supports the passenger hypothesis, but the relative roles of the factors structuring the two groups clearly differed, leading to an apparent decoupling of the two assemblages at the relatively small scale of this study. Community phylogenetic structure in AMF suggests an important role of within-assemblage interactions

When Too Much Is Not Enough: Obsessive-Compulsive Disorder as a Pathology of Stopping, Rather than Starting

Background: In obsessive-compulsive disorder (OCD), individuals feel compelled to repeatedly perform security-related behaviors, even though these behaviours seem excessive and unwarranted to them. The present research investigated two alternative ways of explaining such behavior: (1) a dysfunction of activation—a starting problem—in which the level of excitation in response to stimuli suggesting potential danger is abnormally strong; versus (2) a dysfunction of termination— a stopping problem—in which the satiety-like process for shutting down security-related thoughts and actions is abnormally weak. Method: In two experiments, 70 patients with OCD (57 with washing compulsions, 13 with checking compulsions) and 72 controls were exposed to contamination cues—immersing a hand in wet diapers —and later allowed to wash their hands, first limited to 30 s and then for as long as desired. The intensity of activation of security motivation was measured objectively by change in respiratory sinus arrythmia. Subjective ratings (e.g., contamination) and behavioral measures (e.g., duration of hand washing) were also collected. Results: Compared to controls, OCD patients with washing compulsions did not differ significantly in their levels of initial activation to the threat of contamination; however, they were significantly less able to reduce this activation by engaging in the corrective behavior of hand-washing. Further, the deactivating effect of hand-washing in OCD patients with checkin

DETORQUEO, QUIRKY, and ZERZAUST Represent Novel Components Involved in Organ Development Mediated by the Receptor-Like Kinase STRUBBELIG in Arabidopsis thaliana

Intercellular signaling plays an important role in controlling cellular behavior in apical meristems and developing organs in plants. One prominent example in Arabidopsis is the regulation of floral organ shape, ovule integument morphogenesis, the cell division plane, and root hair patterning by the leucine-rich repeat receptor-like kinase STRUBBELIG (SUB). Interestingly, kinase activity of SUB is not essential for its in vivo function, indicating that SUB may be an atypical or inactive receptor-like kinase. Since little is known about signaling by atypical receptor-like kinases, we used forward genetics to identify genes that potentially function in SUB-dependent processes and found recessive mutations in three genes that result in a sub-like phenotype. Plants with a defect in DETORQEO (DOQ), QUIRKY (QKY), and ZERZAUST (ZET) show corresponding defects in outer integument development, floral organ shape, and stem twisting. The mutants also show sub-like cellular defects in the floral meristem and in root hair patterning. Thus, SUB, DOQ, QKY, and ZET define the STRUBBELIG-LIKE MUTANT (SLM) class of genes. Molecular cloning of QKY identified a putative transmembrane protein carrying four C2 domains, suggesting that QKY may function in membrane trafficking in a Ca2+-dependent fashion. Morphological analysis of single and all pair-wise double-mutant combinations indicated that SLM genes have overlapping, but also distinct, functions in plant organogenesis. This notion was supported by a systematic comparison of whole-genome transcript profiles during floral development, which molecularly defined common and distinct sets of affected processes in slm mutants. Further analysis indicated that many SLM-responsive genes have functions in cell wall biology, hormone signaling, and various stress responses. Taken together, our data suggest that DOQ, QKY, and ZET contribute to SUB-dependent organogenesis and shed light on the mechanisms, which are dependent on signaling through the atypical receptor-like kinase SUB