A. Ratneswaran

Osteoarthritis year in review 2014: mechanics--basic and clinical studies in osteoarthritis.

The purpose of this review was to highlight recent research in mechanics and osteoarthritis (OA) by summarizing results from selected studies spanning basic and clinical research methods. Databases were searched from January 2013 through to March 2014. Working in pairs, reviewers selected 67 studies categorized into four themes--mechanobiology, ambulatory mechanics, biomechanical interventions and mechanical risk factors. Novel developments in mechanobiology included the identification of cell signaling pathways that mediated cellular responses to loading of articular cartilage. Studies in ambulatory mechanics included an increased focus on instrumented knee implants and progress in computational models, both emphasizing the importance of muscular contributions to load. Several proposed biomechanical interventions (e.g., shoe insoles and knee braces) produced variable changes in external knee joint moments during walking, while meta-analysis of randomized clinical trials did not support the use of lateral wedge insoles for decreasing pain. Results from high quality randomized trials suggested diet with or without exercise decreased indicators of knee joint load during walking, whereas similar effects from exercise alone were not detected with the measures used. Data from longitudinal cohorts suggested mechanical alignment was a risk factor for incidence and progression of OA, with the mechanism involving damage to the meniscus. In combination, the basic and clinical studies highlight the importance of considering multiple contributors to joint loading that can evoke both protective and damaging responses. Although challenges clearly exist, future studies should strive to integrate basic and clinical research methods to gain a greater understanding of the interactions among mechanical factors in OA and to develop improved preventive and therapeutic strategies.

Repeated exposure to high-frequency low-amplitude vibration induces degeneration of murine intervertebral discs and knee joints.

High‐frequency, low‐amplitude whole‐body vibration (WBV) is being used to treat a range of musculoskeletal disorders; however, there is surprisingly limited knowledge regarding its effect(s) on joint tissues. This study was undertaken to examine the effects of repeated exposure to WBV on bone and joint tissues in an in vivo mouse model.

Peroxisome Proliferator–Activated Receptor δ Promotes the Progression of Posttraumatic Osteoarthritis in a Mouse Model

Osteoarthritis (OA) is a serious disease of the entire joint, characterized by articular cartilage degeneration, subchondral bone changes, osteophyte formation, and synovial hyperplasia. Currently, there are no pharmaceutical treatments that can slow the disease progression, resulting in greatly reduced quality of life for patients and the need for joint replacement surgeries in many cases. The lack of available treatments for OA is partly due to our incomplete understanding of the molecular mechanisms that promote disease initiation and progression. The purpose of the present study was to examine the role of the nuclear receptor peroxisome proliferator–activated receptor δ (PPARδ) as a promoter of cartilage degeneration in a mouse model of posttraumatic OA.

Nuclear receptors regulate lipid metabolism and oxidative stress markers in chondrocytes

Joint homeostasis failure can result in osteoarthritis (OA). Currently, there are no treatments to alter disease progression in OA, but targeting early changes in cellular behavior has great potential. Recent data show that nuclear receptors contribute to the pathogenesis of OA and could be viable therapeutic targets, but their molecular mechanisms in cartilage are incompletely understood. This study examines global changes in gene expression after treatment with agonists for four nuclear receptor implicated in OA (LXR, PPARδ, PPARγ, and RXR). Murine articular chondrocytes were treated with agonists for LXR, PPARδ, PPARγ, or RXR and underwent microarray, qPCR, and cellular lipid analyses to evaluate changes in gene expression and lipid profile. Immunohistochemistry was conducted to compare two differentially expressed targets (Txnip, Gsta4) in control and cartilage-specific PPARδ knockout mice subjected to surgical destabilization of the medial meniscus (DMM). Nuclear receptor agonists induced different gene expression profiles with many responses affecting lipid metabolism. LXR activation downregulated gene expression of proteases involved in OA, whereas RXR agonism decreased expression of ECM components and increased expression of Mmp13. Functional assays indicate increases in cell triglyceride accumulation after PPARγ, LXR, and RXR agonism but a decrease after PPARδ agonism. PPARδ and RXR downregulate the antioxidant Gsta4, and PPARδ upregulates Txnip. Wild-type, but not PPARδ-deficient mice, display increased staining for Txnip after DMM. Collectively, these data demonstrate that nuclear receptor activation in chondrocytes primarily affects lipid metabolism. In the case of PPARδ, this change might lead to increased oxidative stress, possibly contributing to OA-associated changes.Key messageNuclear receptors regulate metabolic genes in chondrocytes.Nuclear receptors affect triglyceride levels.PPARδ mediates regulation of oxidative stress markers.Nuclear receptors are promising therapeutic targets for osteoarthritis.

Nuclear receptors as potential drug targets in osteoarthritis

HighlightsNuclear receptors (NR) are ligand‐activated transcription factors.NRs are well‐characterized pharmacologically and are promising drug targets for OA.Recent studies have implicated a number of NRs in various forms of OA.Further studies are needed to refine NR ligands for OA treatment. &NA; Osteoarthritis is amongst the major causes of disability worldwide, but no medications that can slow or stop progression of this disorder have been identified. Recent evidence suggests roles for a variety of members of the nuclear receptor family of ligand‐activated transcription factors in various forms of osteoarthritis. Since nuclear receptors are amongst the major classes of drug targets, these studies suggest that modulators of nuclear receptor activity might provide novel strategies to treat osteoarthritis. This review focuses on recent advances in our understanding of the role of nuclear receptors in osteoarthritis onset and progression, as well as their therapeutic implications. Future studies should continue to examine the possible roles of additional nuclear receptors in the pathophysiology of different types of osteoarthritis.

A top-notch dilemma: The complex role of NOTCH signaling in osteoarthritis

Whether NOTCH signaling induces maintenance or degradation of joint cartilage depends on signal strength and duration. A study by Liu et al. in the current issue of Science Signaling explores the complex dual role of NOTCH in the etiology of osteoarthritis by comparing gain-of-function mouse models representing aberrant pathological signaling and transient physiological signaling.