Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis - PubMed (original) (raw)

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

Mary B Goldring. Ther Adv Musculoskelet Dis. 2012 Aug.

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.

Keywords: articular cartilage; chondrogenesis; inflammation; mouse models; osteoarthritis.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Signaling pathways that converge on matrix metalloproteinase13 (MMP13) gene transcription in chondrocytes. Binding of the receptor tyrosine kinase, discoidin domain receptor (DDR) 2, to native type II collagen results in activation of RAS/RAF/MEK/extracellular-regulated kinase (ERK) signaling in a manner independent of integrin- or cytokine-induced signaling. Interleukin (IL)-1, toll-like receptor (TLR) ligand, reactive oxygen species (ROS), advanced glycation endproducts (AGEs) interact with the cell through distinct receptors that transduce phosphorylation events via cytoplasmic interactions initiating various protein kinase cascades. The major pathways involve activation of MAP triple kinases (MTK), MAP kinase kinases (MKKs) 3/6 and 4/7, and p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), which lead to activation of activator protein 1 (AP-1) (cFos/cJun), Runx2, E Twenty Six (ETS) factors, HIF2α, and C/EBPβ, among other transcription factors; and inhibitor of κB (IκB) kinases (IKK) α and β, leading to activation of nuclear factor kappa B (NFκB) and its translocation to the nucleus. The responses of the target gene, MMP13, depend on the presence of DNA sequences within its promoter that bind to the various transcription factors.

Figure 2.

Figure 2.

Strategies for studying mechanisms of osteoarthritis. The upper left panels show Safranin O/Fast green-stained human cartilage sections from a normal individual and a patient with osteoarthritis (OA) (arrows mark surface fibrillations and duplicated tidemark, derived from the tibial plateau [lower left panel] of a patient who underwent total knee replacement surgery (the medial side on the right is more affected than the lateral side). The upper right panels show Safranin O/Fast green-stained murine cartilage sections from knee joints left unoperated (control) or subjected to destabilization of the medial meniscus (DMM) surgery. Differentially regulated proteins and genes are identified in both the clinical material and the preclinical model and mechanisms are further studied in cell culture models of isolated chondrocytes in three-dimensional pellet or high-density monolayers.

Similar articles

Cited by

References

    1. Abdollahi-Roodsaz S., Joosten L.A., Koenders M.I., Devesa I., Roelofs M.F., Radstake T.R., et al. (2008) Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest 118: 205–216 - PMC - PubMed
    1. Aigner T., Fundel K., Saas J., Gebhard P.M., Haag J., Weiss T., et al. (2006) Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis Rheum 54: 3533–3544 - PubMed
    1. Allen K.D., Griffin T.M., Rodriguiz R.M., Wetsel W.C., Kraus V.B., Huebner J.L., et al. (2009) Decreased physical function and increased pain sensitivity in mice deficient for type IX collagen. Arthritis Rheum 60: 2684–2693 - PMC - PubMed
    1. Alsalameh S., Amin R., Gemba T., Lotz M. (2004) Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum 50: 1522–1532 - PubMed
    1. Anderson H.C., Mulhall D., Garimella R. (2010) Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis. Lab Invest 90: 1549–1557 - PubMed

LinkOut - more resources