For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Matrix Metalloproteinases: A Review

In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors (such as genetics, dietary intake, estrogen use, and bone density) and of local biomechanical factors (such as muscle weakness, obesity, and joint laxity). These risk factors are particularly important in weightbearing joints, and modifying them may present opportunities for prevention of osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 1 of a two-part summary of a National Institutes of Health conference. The conference brought together experts on osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 1 focuses on a new understanding of what osteoarthritis is and on risk factors that predispose to disease occurrence. It concludes with a discussion of the impact of osteoarthritis on disability. Ann Intern Med. 2000;133:635-646. www.annals.org For author affiliations and current addresses, see end of text.

/pdf/osteoarthritis-new-insights-part-1-the-disease-and-its-risk-2p0wtgll5h.pdf

Osteoarthritis: New Insights Part 1: The Disease and Its Risk Factors

https://www.cell.com/cell/pdf/S0092-8674(13)00201-8.pdf

Long Noncoding RNAs: Cellular Address Codes in Development and Disease

Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability in older adults (1) Often OA is referred to as degenerative joint disease “(DJD)” This is a misnomer because OA is not simply a process of wear and tear but rather abnormal remodeling of joint tissues driven by a host of inflammatory mediators within the affected joint The most common risk factors for OA include age, gender, prior joint injury, obesity, genetic predisposition, and mechanical factors, including malalignment and abnormal joint shape (2, 3) Despite the multifactorial nature of OA, the pathological changes seen in osteoarthritic joints have common features that affect the entire joint structure resulting in pain, deformity and loss of function

The pathologic changes seen in OA joints (Figures 1 and ​and2)2) include degradation of the articular cartilage, thickening of the subchondral bone, osteophyte formation, variable degrees of synovial inflammation, degeneration of ligaments and, in the knee, the menisci, and hypertrophy of the joint capsule There can also be changes in periarticular muscles, nerves, bursa, and local fat pads that may contribute to OA or the symptoms of OA The findings of pathological changes in all of the joint tissues are the impetus for considering OA as a disease of the joint as an organ resulting in “joint failure” In this review, we will summarize the key features of OA in the various joint tissues affected and provide an overview of the basic mechanisms currently thought to contribute to the pathological changes seen in these tissues






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Figure 1


Sagittal inversion recovery (A–C) and coronal fast spin echo (D–F) images illustrating the magnetic resonance imaging findings of osteoarthritis (A) reactive synovitis (thick white arrow), (B) subchondral cyst formation (white arrow), (C) bone marrow edema (thin white arrows), (D) partial thickness cartilage wear (thick black arrow), (E–F) full thickness cartilage wear (thin black arrows), subchondral sclerosis (arrowhead) and marginal osteophyte formation (double arrow) Image courtesy of Drs Hollis Potter and Catherine Hayter, Hospital for Special Surgery, New York, NY

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.34453

Osteoarthritis: A Disease of the Joint as an Organ

Purpose of review
This review focuses on the novel stress-induced and proinflammatory mechanisms underlying the pathogenesis of osteoarthritis, with particular attention to the role of synovitis and the contributions of other joint tissues to cellular events that lead to the onset and progression of the disease and irreversible cartilage damage.

Inflammation in osteoarthritis

Chondrogenesis is the earliest phase of skeletal development, involving mesenchymal cell recruitment and migration, condensation of progenitors, and chondrocyte differentiation, and maturation and resulting in the formation of cartilage and bone during endochondral ossification. This process is controlled exquisitely by cellular interactions with the surrounding matrix, growth and differentiation factors, and other environmental factors that initiate or suppress cellular signaling pathways and transcription of specific genes in a temporal-spatial manner. Vertebrate limb development is controlled by interacting patterning systems involving prominently the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and hedgehog pathways. Both positive and negative signaling kinases and transcription factors, such as Sox9 and Runx2, and interactions among them determine whether the differentiated chondrocytes remain within cartilage elements in articular joints or undergo hypertrophic maturation prior to ossification. The latter process requires extracellular matrix remodeling and vascularization controlled by mechanisms that are not understood completely. Recent work has revealed novel roles for mediators such as GADD45beta, transcription factors of the Dlx, bHLH, leucine zipper, and AP-1 families, and the Wnt/beta-catenin pathway that interact at different stages during chondrogenesis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcb.20652

The control of chondrogenesis.

The articular surface plays an essential role in load transfer across the joint, and conditions that produce increased load transfer or altered patterns of load distribution accelerate the development of osteoarthritis (OA). Current knowledge segregates the risk factors into two fundamental mechanisms related to the adverse effects of "abnormal" loading on normal cartilage or "normal" loading on abnormal cartilage. Although chondrocytes can modulate their functional state in response to loading, their capacity to repair and modify the surrounding extracellular matrix is limited in comparison to skeletal cells in bone. This differential adaptive capacity underlies the more rapid appearance of detectable skeletal changes, especially after acute injuries that alter joint mechanics. The imbalance in the adaptation of the cartilage and bone disrupts the physiological relationship between these tissues and further contributes to OA pathology. This review focuses on the specific articular cartilage and skeletal features of OA and the putative mechanisms involved in their pathogenesis.

Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis

Osteoarthritis (OA) is a slowly progressive degenerative disease characterized by gradual loss of articular cartilage. Since the OA lesion is often localized to weight-bearing cartilage or to sites of trauma, repetitive mechanical injury has been proposed as the critical signal for the initiation and progression of OA. It is now generally accepted that the chondrocyte is the target of these abnormal biomechanical factors, and that biochemical and genetic factors also contribute to alterations in the normal functional activities of these cells. Although OA has been regarded primarily as a noninflammatory arthropathy, symptoms of local inflammation and synovitis are present in many patients and have been observed in animal models of OA. Even in the absence of classic inflammation, which is characterized by infiltration of neutrophils and macrophages into joint tissues, elevated levels of inflammatory cytokines have been measured in OA synovial fluid. Although the OA cartilage lesion is present at sites remote from the synovium, the fibroblastand macrophage-like synovial cells, as well as the chondrocyte itself, are potential sources of cytokines that could induce chondrocytes to synthesize and secrete cartilagedegrading proteases, cytokines, and other inflammatory mediators. These synoviumand chondrocyte-derived products represent potential targets for the development of therapeutic agents, such as proteinase inhibitors, cytokine antagonists, and cytokine receptor blocking antibodies, which could be used to prevent or retard the progression of the OA articular lesion. This review will focus on evidence that implicates chondrocyte responses to cytokines in the pathogenesis of OA and will discuss the potential therapeutic applications of these findings.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28200009%2943%3A9%3C1916%3A%3AAID-ANR2%3E3.0.CO%3B2-I

Mary B. Goldring

Papers

Osteoarthritis: A Disease of the Joint as an Organ

Inflammation in osteoarthritis

The control of chondrogenesis.

Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis

The role of the chondrocyte in osteoarthritis