The repair of large bone defects remains a major clinical orthopaedic challenge. Bone is a highly vascularised tissue reliant on the close spatial and temporal connection between blood vessels and bone cells to maintain skeletal integrity. Angiogenesis thus plays a pivotal role in skeletal development and bone fracture repair. Current procedures to repair bone defects and to provide structural and mechanical support include the use of grafts (autologous, allogeneic) or implants (polymeric or metallic). These approaches face significant limitations due to insufficient supply, potential disease transmission, rejection, cost and the inability to integrate with the surrounding host tissue.
It is widely accepted that the likelihood of offspring developing heart disease, stroke, or diabetes in later life, is infl uenced by the their in utero environment and maternal nutrition. There is increasing epidemiological evidence that osteoporosis in the offspring may also be infl uenced by the mother's nutrition during pregnancy. This review provides evidence from a range of animal models that supports the epidemiological data; suggesting that lifelong bone development and growth in offspring is determined during gestation.
In contrast to traditional approaches to fracture risk assessment using clinical risk factors and bone mineral density (BMD), a new technique, reference point microindentation (RPI), permits direct assessment of bone quality; in vivo tibial RPI measurements appear to discriminate patients with a fragility fracture from controls. However, it is unclear how this relates to the site of the most clinically devastating fracture, the femoral neck, and whether RPI provides information complementary to that from existing assessments. Femoral neck samples were collected at surgery after low-trauma hip fracture (n ¼ 46; 17 male; aged 83 [interquartile range 77-87] years) and compared, using RPI (Biodent Hfc), with 16 cadaveric control samples, free from bone disease (7 male; aged 65 years). A subset of fracture patients returned for dual-energy X-ray absorptiometry (DXA) assessment (Hologic Discovery) and, for the controls, a micro-computed tomography setup (HMX, Nikon) was used to replicate DXA scans. The indentation depth was greater in femoral neck samples from osteoporotic fracture patients than controls (p < 0.001), which persisted with adjustment for age, sex, body mass index (BMI), and height (p < 0.001) but was site-dependent, being less pronounced in the inferomedial region. RPI demonstrated good discrimination between fracture and controls using receiver-operating characteristic (ROC) analyses (area under the curve [AUC] ¼ 0.79 to 0.89), and a model combining RPI to clinical risk factors or BMD performed better than the individual components (AUC ¼ 0.88 to 0.99). In conclusion, RPI at the femoral neck discriminated fracture cases from controls independent of BMD and traditional risk factors but dependent on location. The clinical RPI device may, therefore, supplement risk assessment and requires testing in prospective cohorts and comparison between the clinically accessible tibia and the femoral neck.
chondrocytes (ACs) and its regulatory mechanisms remain unclear. This study aimed to explore epigenetic regulatory mechanisms of age-related SOX9 expression in ACs of mice, spanning from the embryonic stage to 18 months of age. Methods: The hip and shoulder joints of wild type BALB/c mice were harvested at embryonic day 16.5 and 1, 2, 6, 12 and 18 months for histopathological and immunohistochemical analyses. Femoral and humeral head cartilage from the same age groups was used for chondrocyte isolation, gene expression, methylated DNA immunoprecipitation or chromatin immunoprecipitation assays to examine epigenetic changes in the promoter region of the Sox9 gene. siRNA-mediated knockdown of the histone lysine-specific demethylases-1 gene (Lsd1) and 5-azacytidine treatment were performed in cultured ACs. Results: Sox9 mRNA and protein were highly expressed in ACs during joint development but significantly decreased at 2-18 months of age. No histopathological features of osteoarthritis were observed in examined joints by 18 months. Epigenetic DNA methylation and histone methylation are both associated with the age-dependent SOX9 expression. Knockdown of Lsd1 is sufficient to up-regulate SOX9 expression in ACs of adult mice through increased recruitment of H3K4me2 (a histone modification for transcriptional activation) in the promoter region of the Sox9 gene. However, the reduction of DNA methylation in the Sox9 promoter region induced by 5-azacytidine treatment in cultured ACs did not increase Sox9 expression. The data suggest that reduction of SOX9 expression in ACs of adult mice is primarily regulated by H3K4me2. Conclusions: These results suggest that SOX9 expression in mouse ACs is significantly decreased after the completion of joint development due to reduced demands for SOX9. This developmental switch in SOX9 expression in mouse articular cartilage is primarily regulated by epigenetic histone methylation.
The development of new bone formation strategies offers tremendous therapeutic implications in a variety of musculoskeletal diseases. One approach involves harnessing the regenerative capacity of osteoprogenitor bone cells in combination with biomimetic scaffolds generated from appropriate scaffold matrices and osteoinductive factors. The aims of our study were to test the efficacy of two innovative osteoinductive agents: the osteoblast stimulating factor-1 (osf-1), an extracellular matrix-associated protein, and osteoinductive extracts of Saos-2 cells on human osteoprogenitor cells. Saos-2 extracted osteoinductive factors significantly stimulated alkaline phosphatase specific activity in basal and osteogenic conditions. Osf-1 significantly stimulated chemotaxis, total colony formation, alkaline phosphatase-positive colony formation, and alkaline phosphatase specific activity at concentrations as low as 10 pg/ml compared with control cultures. Osteoinductive factors present in Saos-2 cell extracts and osf-1 promoted adhesion, migration, expansion, and differentiation of human osteoprogenitor cells on 3-D scaffolds. The successful generation of 3-D biomimetic structures incorporating osf-1 or osteoinductive factors from Saos-2 cells indicates their potential for de novo bone formation that exploits cell-matrix interactions.
The cover shows biomineralized polysaccharide capsules with specifiable make‐up, which can provide microenvironments for stabilization, growth, and differentiation of human cell types, as reported by Oreffo and co‐workers on p. 917. The capsules are amenable to complexation with a range of bioactive molecules and cells, offering tremendous potential as multifunctional scaffolds and delivery vehicles in tissue regeneration of hard and soft tissues.
The construction of biomimetic microenvironments with specific chemical and physical cues for the organization and modulation of a variety of cell populations is of key importance in tissue engineering. We show that a range of human cell types, including promyoblasts, chondrocytes, adipocytes, adenovirally transduced osteoprogenitors, immunoselected mesenchymal stem cells, and the osteogenic factor, rhBMP‐2 (BMP: bone morphogenic protein), can be successfully encapsulated within mineralized polysaccharide capsules without loss of function in vivo. By controlling the extent of mineralization within the alginate/chitosan shell membrane, degradation of the shell wall and release of cells or rhBMP‐2 into the surrounding medium can be regulated. In addition, we describe for the first time the ability to generate bead‐in‐bead capsules consisting of spatially separated cell populations and temporally separated biomolecule release, entrapped within alginate/chitosan shells of variable thickness, mineralization, and stability. Such materials offer significant potential as multifunctional scaffolds and delivery vehicles in tissue regeneration of hard and soft tissues.
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