The effect of oxygen tension on human articular chondrocyte matrix synthesis: integration of experimental and computational approaches.

Significant oxygen gradients occur within tissue engineered cartilaginous constructs. Although oxygen tension is an important limiting parameter in the development of new cartilage matrix, its precise role in matrix formation by chondrocytes remains controversial, primarily due to discrepancies in the experimental setup applied in different studies. In this study, the specific effects of oxygen tension on the synthesis of cartilaginous matrix by human articular chondrocytes were studied using a combined experimental-computational approach in a "scaffold-free" 3D pellet culture model. Key parameters including cellular oxygen uptake rate were determined experimentally and used in conjunction with a mathematical model to estimate oxygen tension profiles in 21-day cartilaginous pellets. A threshold oxygen tension (pO2 ≈ 8% atmospheric pressure) for human articular chondrocytes was estimated from these inferred oxygen profiles and histological analysis of pellet sections. Human articular chondrocytes that experienced oxygen tension below this threshold demonstrated enhanced proteoglycan deposition. Conversely, oxygen tension higher than the threshold favored collagen synthesis. This study has demonstrated a close relationship between oxygen tension and matrix synthesis by human articular chondrocytes in a "scaffold-free" 3D pellet culture model, providing valuable insight into the understanding and optimization of cartilage bioengineering approaches.

Skeletal stem cells and bone regeneration: translational strategies from bench to clinic.

Clinical imperatives for new bone to replace or restore the function of traumatized or bone lost as a consequence of age or disease has led to the need for therapies or procedures to generate bone for skeletal applications. Tissue regeneration promises to deliver specifiable replacement tissues and the prospect of efficacious alternative therapies for orthopaedic applications such as non-union fractures, healing of critical sized segmental defects and regeneration of articular cartilage in degenerative joint diseases. In this paper we review the current understanding of the continuum of cell development from skeletal stem cells, osteoprogenitors through to mature osteoblasts and the role of the matrix microenvironment, vasculature and factors that control their fate and plasticity in skeletal regeneration. Critically, this review addresses in vitro and in vivo models to investigate laboratory and clinical based strategies for the development of new technologies for skeletal repair and the key translational points to clinical success. The application of developmental paradigms of musculoskeletal tissue formation specifically, understanding developmental biology of bone formation particularly in the adult context of injury and disease will, we propose, offer new insights into skeletal cell biology and tissue regeneration allowing for the critical integration of stem cell science, tissue engineering and clinical applications. Such interdisciplinary, iterative approaches will be critical in taking patient aspirations to clinical reality.

A duality in the roles of reactive oxygen species with respect to bone metabolism.

BACKGROUND: Rampant production in skeletal abnormalities can lead to hyperoxidant stress though the production of "reactive oxygen species" (ROS) by osteoclasts, which assist in bone remodeling under physiological conditions. METHODS: Thirty cases each of post-menopausal osteoporosis, renal osteodystrophy and bone fractures constituted the test groups. Thirty healthy subjects made up the control group. Serum total alkaline phosphatase served as an index of osteoblastic activity. Serum calcium and phosphorous indicated bone remodeling status. Serum superoxide dismutase, glutathione peroxidase and glutathione reductase represented the enzymatic antioxidants. RESULTS: Mean values for malondialdehyde were significantly elevated (P<0.001) in test groups, indicating enhanced osteoclastic activity. Significantly depressed (P<0.001) activities of superoxide dismutase and glutathione peroxidase reinforced hyperoxidant stress. Mean values of glutathione reductase remained unaltered. Diminished osteoblastic activity in post-menopausal osteoporosis was indicated by depressed alkaline phosphatase (P<0.001). Increased serum calcium (P<0.001) and decreased serum phosphorous (P<0.001) in renal osteodystrophy indicated compensatory hyperparathyroidism. CONCLUSIONS: The findings indicate that ROS have a major role to play in bone metabolism.