Cartilage regeneration for treatment of osteoarthritis: a paradigm for nonsurgical intervention

Abstract

Osteoarthritis (OA) is associated with articular cartilage abnormalities and affects people of older age: preventative or therapeutic treatment measures for OA and related articular cartilage disorders remain challenging. In this perspective review, we have integrated multiple biological, morphological, developmental, stem cell and homeostasis concepts of articular cartilage to develop a paradigm for cartilage regeneration. OA is conceptually defined as an injury of cartilage that initiates chondrocyte activation, expression of proteases and growth factor release from the matrix. This regenerative process results in the local activation of inflammatory response genes in cartilage without migration of inflammatory cells or angiogenesis. The end results are catabolic and anabolic responses, and it is the balance between these two outcomes that controls remodelling of the matrix and regeneration. A tantalizing clinical clue for cartilage regrowth in OA joints has been observed in surgically created joint distraction. We hypothesize that cartilage growth in these distracted joints may have a biological connection with the size of organs and regeneration. Therefore we propose a novel, practical and nonsurgical intervention to validate the role of distraction in cartilage regeneration in OA. The approach permits normal wake-up activity while during sleep; the index knee is subjected to distraction with a pull traction device. Comparison of follow-up magnetic resonance imaging (MRI) at 3 and 6 months of therapy to those taken before therapy will provide much-needed objective evidence for the use of this mode of therapy for OA. We suggest that the paradigm presented here merits investigation for treatment of OA in knee joints.

Role of Inflammation and the Immune System in the Progression of Osteoarthritis

“…Likewise, the release of matrix breakdown products into the synovial fluid triggers feedback to cells in the synovium, stimulating further catabolic enzyme production This feed‐forward loop continues to produce catabolic stimulus to the macrophages, and therefore they do not transition to a remodeling phenotype because they continue to receive the “cleanup” signal. By signaling protease digestion around the chondrocytes, the chondrocytes are released from the matrix and attempt to populate the injured site . However, it appears that in particular in the middle and deep zones of cartilage, this repair is too slow and the cell density is too low to overcome the ongoing degradation process .…”

“…By signaling protease digestion around the chondrocytes, the chondrocytes are released from the matrix and attempt to populate the injured site . However, it appears that in particular in the middle and deep zones of cartilage, this repair is too slow and the cell density is too low to overcome the ongoing degradation process . Therefore, the synovial macrophages never get an adequate signal to fully stop the inflammatory cleanup process and continue the cycle of producing matrix‐degrading proteases.…”

Mixed cell therapy of bone marrow-derived mesenchymal stem cells and articular cartilage chondrocytes ameliorates osteoarthritis development

“…[40][41][42] The role of VEGF in angiogenesis driven blood vessel formation in OA is well known 43,44 and it is firmly established that VEGF have pathological role in OA cartilage. 45 ChM-1, on the other hand, inhibits angiogenesis in cartilage 46,47 and its high expression by chondrocytes helps to maintain their avascular phenotype. Our findings indicate that BMSCs, even in chondrogenic culture conditions, will naturally express higher levels of VEGF and lower levels of ChM-1; ACCs, by contrast, express higher levels of ChM-1 and lower levels of VEGF under the same culture conditions.…”

Bone morphogenetic proteins for articular cartilage regeneration

“…contents to maintain structural integrity and strength for joint load and mobility. During normal conditions, articular chondrocytes and subchondral osteoblasts receive mechanical load and strain 5,6 . However, in abnormal conditions, such as mechanical overload or injury, an imbalance between chondrocyte anabolism and catabolism leads to the secretion of pro-inflammatory cytokines and matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), which inhibit angiogenesis.…”