Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis

Abstract

Chondrogenesis occurs as a result of mesenchymal cell condensation and chondroprogenitor cell differentiation. Following chondrogenesis, the chondrocytes remain as resting cells to form the articular cartilage or undergo proliferation, terminal differentiation to chondrocyte hypertrophy, and apoptosis in a process termed endochondral ossification, whereby the hypertrophic cartilage is replaced by bone. Human adult articular cartilage is a complex tissue of matrix proteins that varies from superficial to deep layers and from loaded to unloaded zones. A major challenge to efforts to repair cartilage by stem cell-based and other tissue-engineering strategies is the inability of the resident chondrocytes to lay down a new matrix with the same properties as it had when it was formed during development. Thus, understanding and comparing the mechanisms of cartilage remodeling during development, osteoarthritis (OA), and aging may lead to more effective strategies for preventing cartilage damage and promoting repair. The pivotal proteinase that marks OA progression is matrix metalloproteinase 13 (MMP-13), the major type II collagen-degrading collagenase, which is regulated by both stress and inflammatory signals. We and other investigators have found that there are common mediators of these processes in human OA cartilage. We also observe temporal and spatial expression of these mediators in early through late stages of OA in mouse models and are analyzing the consequences of knockout or transgenic overexpression of critical genes. Since the chondrocytes in adult human cartilage are normally quiescent and maintain the matrix in a low turnover state, understanding how they undergo phenotypic modulation and promote matrix destruction and abnormal repair in OA may to lead to identification of critical targets for therapy to block cartilage damage and promote effective cartilage repair.

Mesenchyme-specific Knockout of ESET Histone Methyltransferase Causes Ectopic Hypertrophy and Terminal Differentiation of Articular Chondrocytes

“…One possible mechanism for the development of osteoarthritis is the failure of articular chondrocytes to maintain their latent phenotype. In such a model, articular chondrocytes become mitotically active, proliferate, and express proteins such as type-X collagen, alkaline phosphatase, and matrix metalloproteinase-13 (MMP-13), 3 proteins that are indicative of chondrocyte terminal differentiation. This is a process reminiscent of growth plate chondrocytes during endochondral ossification (1,2).…”

“…This is a process reminiscent of growth plate chondrocytes during endochondral ossification (1,2). It should be pointed out, however, that osteoarthritis-like changes in joints may also occur without evidence of chondrocyte hypertrophy but instead are caused by inflammatory insults, increases in metabolic stress, and reactive oxygen species or, merely the accumulated effects of cell death (3,4).…”

The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration

“…Sox9 and Runt-related transcription factor2 (Runx2) are the principal regulators, but they differ in function; while Sox9 leads to articular cartilage formation, Runx2 is involved in hypertrophic maturation of the cells [18]. Both factors are expressed throughout the entire chondrogenic process, starting from mesenchymal condensation and ending with terminal chondrocyte hypertrophy.…”

“…Chondroprogenitor cell differentiation reveals the expression of cartilage-specific collagens (types II, IX and XI). Ultimately, the proliferating chondrocytes express type VI collagen as well as matrilin 1, while type X collagen indicates the hypertrophic zone [18].…”

Formation of synovial joints and articular cartilage

“…According to the traditional views articular cartilage represents part of embryonic epiphyses that are not replaced by bone through endochondral ossification [18,26]. This view was challenged by several authors who assumed that articular cartilage is formed by the cells lying at the periphery of the cavitated joint and derived from the cells of interzone [4,8,28].…”