Human Sclera Maintains Common Characteristics with Cartilage throughout Evolution

BACKGROUND: The sclera maintains and protects the eye ball, which receives visual inputs. Although the sclera does not contribute significantly to visual perception, scleral diseases such as refractory scleritis, scleral perforation and pathological myopia are considered incurable or difficult to cure. The aim of this study is to identify characteristics of the human sclera as one of the connective tissues derived from the neural crest and mesoderm. METHODOLOGY/PRINCIPAL FINDINGS: We have demonstrated microarray data of cultured human infant scleral cells. Hierarchical clustering was performed to group scleral cells and other mesenchymal cells into subcategories. Hierarchical clustering analysis showed similarity between scleral cells and auricular cartilage-derived cells. Cultured micromasses of scleral cells exposed to TGF-betas and BMP2 produced an abundant matrix. The expression of cartilage-associated genes, such as Indian hedge hog, type X collagen, and MMP13, was up-regulated within 3 weeks in vitro. These results suggest that human 'sclera'-derived cells can be considered chondrocytes when cultured ex vivo. CONCLUSIONS/SIGNIFICANCE: Our present study shows a chondrogenic potential of human sclera. Interestingly, the sclera of certain vertebrates, such as birds and fish, is composed of hyaline cartilage. Although the human sclera is not a cartilaginous tissue, the human sclera maintains chondrogenic potential throughout evolution. In addition, our findings directly explain an enigma that the sclera and the joint cartilage are common targets of inflammatory cells in rheumatic arthritis. The present global gene expression database will contribute to the clarification of the pathogenesis of developmental diseases such as high myopia

Bone refilling in cortical bone multicellular units: Insights into tetracycline double labelling from a computational model

Bone remodelling is carried out by `bone multicellular units' (BMUs) in which active osteoclasts and active osteoblasts are spatially and temporally coupled. The refilling of new bone by osteoblasts towards the back of the BMU occurs at a rate that depends both on the number of osteoblasts and on their secretory activity. In cortical bone, a linear phenomenological relationship between matrix apposition rate (MAR) and BMU cavity radius is found experimentally. How this relationship emerges from the combination of complex, nonlinear regulations of osteoblast number and secretory activity is unknown. Here, we extend our previous mathematical model of cell development within a single BMU to investigate how osteoblast number and osteoblast secretory activity vary along the BMU's closing cone. MARs predicted by the model are compared with data from tetracycline double labelling experiments. We find that the linear phenomenological relationship observed in these experiments between MAR and BMU cavity radius holds for most of the refilling phase simulated by our model, but not near the start and end of refilling. This suggests that at a particular bone site undergoing remodelling, bone formation starts and ends rapidly. Our model also suggests that part of the observed cross-sectional variability in tetracycline data may be due to different bone sites being refilled by BMUs at different stages of their lifetime. The different stages of a BMU's lifetime depend on whether the cell populations within the BMU are still developing or have reached a quasi-steady state while travelling through bone. We find that due to their longer lifespan, active osteoblasts reach a quasi-steady distribution more slowly than active osteoclasts. We suggest that this fact may locally enlarge the Haversian canal diameter (due to a local lack of osteoblasts compared to osteoclasts) near the BMU's point of origin.Comment: 16 pages, 6 figures, 3 tables. V3: minor changes: added 2 paragraphs (BMU cavity in Section 2 and Model Robustness in Section 4), references [52,54

Synergistic activity of polarised osteoblasts inside condensations cause their differentiation

Condensation of pre-osteogenic, or pre-chondrogenic, cells is the first of a series of processes that initiate skeletal development. We present a validated, novel, three-dimensional agent-based model of in vitro intramembranous osteogenic condensation. The model, informed by system heterogeneity and relying on an interaction-reliant strategy, is shown to be sensitive to 'rules' capturing condensation growth and can be employed to track activity of individual cells to observe their macroscopic impact. It, therefore, makes available previously inaccessible data, offering new insights and providing a new context for exploring the emergence, as well as normal and abnormal development, of osteogenic structures. Of the several stages of condensation we investigate osteoblast 'burial' within the osteoid they deposit. The mechanisms underlying entrapment - required for osteoblasts to differentiate into osteocytes - remain a matter of conjecture with several hypotheses claiming to capture this important transition. Computational examination of this transition indicates that osteoblasts neither turn off nor slow down their matrix secreting genes - a widely held view; nor do they secrete matrix randomly. The model further reveals that osteoblasts display polarised behaviour to deposit osteoid. This is both an important addition to our understanding of condensation and an important validation of the model's utility