Michael B. Ellman

A current review of molecular mechanisms regarding osteoarthritis and pain

Osteoarthritis afflicts millions of individuals across the world resulting in impaired quality of life and increased health costs. To understand this disease, physicians have been studying risk factors, such as genetic predisposition, aging, obesity, and joint malalignment; however have been unable to conclusively determine the direct etiology. Current treatment options are short-term or ineffective and fail to address pathophysiological and biochemical mechanisms involved with cartilage degeneration and the induction of pain in arthritic joints. OA pain involves a complex integration of sensory, affective, and cognitive processes that integrate a variety of abnormal cellular mechanisms at both peripheral and central (spinal and supraspinal) levels of the nervous system Through studies examined by investigators, the role of growth factors and cytokines has increasingly become more relevant in examining their effects on articular cartilage homeostasis and the development of osteoarthritis and osteoarthritis-associated pain. Catabolic factors involved in both cartilage degradation in vitro and nociceptive stimulation include IL-1, IL-6, TNF-α, PGE2, FGF-2 and PKCδ, and pharmacologic inhibitors to these mediators, as well as compounds such as RSV and LfcinB, may potentially be used as biological treatments in the future. This review explores several biochemical mediators involved in OA and pain, and provides a framework for the understanding of potential biologic therapies in the treatment of degenerative joint disease in the future.

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis.

Two members of the fibroblast growth factor (FGF) family, basic FGF (bFGF) and FGF-18, have been implicated in the regulation of articular and intervertebral disc (IVD) cartilage homeostasis. Studies on bFGF from a variety of species have yielded contradictory results with regards to its precise role in cartilage matrix synthesis and degradation. In contrast, FGF-18 is a well-known anabolic growth factor involved in chondrogenesis and articular cartilage repair. In this review, we examined the biological actions of bFGF and FGF-18 in articular and IVD cartilage, the specific cell surface receptors bound by each factor, and the unique signaling cascades and molecular pathways utilized to exert their biological effects. Evidence suggests that bFGF selectively activates FGF receptor 1 (FGFR1) to exert degradative effects in both human articular chondrocytes and IVD tissue via upregulation of matrix-degrading enzyme activity, inhibition of matrix production, and increased cell proliferation resulting in clustering of cells seen in arthritic states. FGF-18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating FGFR3, increasing matrix formation and cell differentiation while inhibiting cell proliferation, leading to dispersed cells surrounded by abundant matrix. The results from in vitro and in vivo studies suggest the potential usefulness of bFGF and FGFR1 antagonists, as well as FGF-18 and FGFR3 agonists, as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future.

Meniscal Root Tears: Significance, Diagnosis, and Treatment

Meniscal root tears, less common than meniscal body tears and frequently unrecognized, are a subset of meniscal injuries that often result in significant knee joint disorders. The meniscus root attachment aids meniscal function by securing the meniscus in place and allowing for optimal shock-absorbing function in the knee. With root tears, meniscal extrusion often occurs, and the transmission of circumferential hoop stresses is impaired. This alters knee biomechanics and kinematics and significantly increases tibiofemoral contact pressure. In recent years, meniscal root tears, which by definition include direct avulsions off the tibial plateau or radial tears adjacent to the root itself, have attracted attention because of concerns that significant meniscal extrusion dramatically inhibits normal meniscal function, leading to a condition biomechanically similar to a total meniscectomy. Recent literature has highlighted the importance of early diagnosis and treatment; fortunately, these processes have been vastly improved by advances in magnetic resonance imaging and arthroscopy. This article presents a review of the clinically relevant anatomic, biomechanical, and functional descriptions of the meniscus root attachments, as well as current strategies for accurate diagnosis and treatment of common injuries to these meniscus root attachments.

Prostaglandin E2 and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis.

OBJECTIVE To elucidate the pathophysiologic links between prostaglandin E(2) (PGE(2)) and osteoarthritis (OA) by characterizing the catabolic effects of PGE(2) and its unique receptors in human adult articular chondrocytes. METHODS Human adult articular chondrocytes were cultured in monolayer or alginate beads with and without PGE(2) and/or agonists of EP receptors, antagonists of EP receptors, and cytokines. Cell survival, proliferation, and total proteoglycan synthesis and accumulation were measured in alginate beads. Chondrocyte-related gene expression and phosphatidylinositol 3-kinase/Akt signaling were assessed by real-time reverse transcription-polymerase chain reaction and Western blotting, respectively, using a monolayer cell culture model. RESULTS Stimulation of human articular chondrocytes with PGE(2) through the EP2 receptor suppressed proteoglycan accumulation and synthesis, suppressed aggrecan gene expression, did not appreciably affect expression of matrix-degrading enzymes, and decreased the type II collagen:type I collagen ratio. EP2 and EP4 receptors were expressed at higher levels in knee cartilage than in ankle cartilage and in a grade-dependent manner. PGE(2) titration combined with interleukin-1 (IL-1) synergistically accelerated expression of pain-associated molecules such as inducible nitric oxide synthase and IL-6. Finally, stimulation with exogenous PGE(2) or an EP2 receptor-specific agonist inhibited activation of Akt that was induced by insulin-like growth factor 1. CONCLUSION PGE(2) exerts an antianabolic effect on human adult articular cartilage in vitro, and EP2 and EP4 receptor antagonists may represent effective therapeutic agents for the treatment of OA.

Basic Fibroblast Growth Factor Activates the MAPK and NFκB Pathways That Converge on Elk-1 to Control Production of Matrix Metalloproteinase-13 by Human Adult Articular Chondrocytes

The pathology of joint destruction is associated with elevated production of basic fibroblast growth factor (bFGF) and matrix metalloproteinase-13 (MMP-13). In osteoarthritic joint disease, expression of bFGF and MMP-13 in chondrocytes and their release into the synovial fluid are significantly increased. We have previously found that the capacity for cartilage repair in human adult articular chondrocytes is severely compromised by minimal exposure to bFGF because bFGF reduces responsiveness to bone morphogenetic protein-7 and insulin-like growth factor-1 and induces MMP-13 through protein kinase Cδ-dependent activation of multiple mitogen-activated protein kinase (MAPK) signaling pathways. Here we show using biochemical and molecular approaches that transcription factor Elk-1, a direct downstream target of MAPK, is a critical transcriptional activator of of MMP-13 by bFGF in human articular chondrocytes. We also provide evidence that Elk-1 is a direct target of NFκB and induces MMP-13 expression upon activation of the NFκB signaling pathway. Taken together, our results suggest that elevated expression of MMP-13 occurs through Elk-1 activation of both MAPK and NFκB signaling pathways, thus revealing a two-pronged biological mechanism by which bFGF controls the production of catabolic enzymes that are associated with excessive degradation of the cartilage matrix in degenerative joint diseases such as osteoarthritis.

Fibroblast Growth Factor Control of Cartilage Homeostasis

Osteoarthritis (OA) and degenerative disc disease (DDD) are similar diseases involving the breakdown of cartilage tissue, and a better understanding of the underlying biochemical processes involved in cartilage degeneration may allow for the development of novel biologic therapies aimed at slowing the disease process. Three members of the fibroblast growth factor (FGF) family, FGF‐2, FGF‐18, and FGF‐8, have been implicated as contributing factors in cartilage homeostasis. The role of FGF‐2 is controversial in both articular and intervertebral disc (IVD) cartilage as it has been associated with species‐ and age‐dependent anabolic or catabolic events. Recent evidence suggests that FGF‐2 selectively activates FGF receptor 1 (FGFR1) to exert catabolic effects in human articular chondrocytes and IVD tissue via upregulation of matrix‐degrading enzyme production, inhibition of extracellular matrix (ECM) accumulation and proteoglycan synthesis, and clustering of cells characteristic of arthritic states. FGF‐18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating the FGFR3 pathway, inducing ECM formation and chondrogenic cell differentiation, and inhibiting cell proliferation. These changes result in dispersed chondrocytes or disc cells surrounded by abundant matrix. The role of FGF‐8 has recently been identified as a catabolic mediator in rat and rabbit articular cartilage, but its precise biological impact on human adult articular cartilage or IVD tissue remains unknown. The available evidence reveals the promise of FGF‐2/FGFR1 antagonists, FGF‐18/FGFR3 agonists, and FGF‐8 antagonists (i.e., anti‐FGF‐8 antibody) as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future. J. Cell. Biochem. 114: 735–742, 2013.

Fracture of the modular femoral neck component in total hip arthroplasty.

The use of modularity, specifically dual modular femoral stems, in total hip arthroplasty has increased in popularity over the past 2 decades. While offering several distinct advantages intraoperatively, the long-term success of adding a second modular junction has yet to be established. One potential complication of increasing modularity is component fracture. We present a case of modular femoral neck prosthesis fracture necessitating revision surgery to treat this complication. Careful preoperative planning during revision of these failures is essential to avoid morbidity and unnecessary subsequent revision surgeries, as demonstrated in this case. The combined effects of crevice and fretting corrosion, large-diameter femoral head, long modular neck, metal-on-metal articulation, patient size, and activity level may have all played integral roles in creating an environment susceptible to this classic pattern of fatigue fracture.

An Epidemiologic Analysis of Clinical Practice Guidelines for Non-Arthroplasty Treatment of Osteoarthritis of the Knee

PURPOSE To analyze the current practice patterns of non-arthroplasty treatment of knee osteoarthritis (OA) and to assess the impact of the American Academy of Orthopaedic Surgeons clinical practice guidelines on the management of OA of the knee, particularly as they relate to the use of arthroscopic treatment. METHODS The United Healthcare Database (2004-2009, 11 million patients, 216 million records) was used for the study and was searched using Boolean language for International Classification of Diseases, Ninth Edition, Clinical Modification and Current Procedural Terminology, fourth revision codes. A reference group was defined as patients treated with knee arthroplasty in 2009 and diagnosed with knee OA in the same record. Clinical practice patterns in the 5 years preceding arthroplasty were analyzed in this group. RESULTS The reference group consisted of 12,806 patients undergoing total knee arthroplasty in 2009 with a documented diagnosis of OA at the time of surgery, with prior nonoperative treatment strategies analyzed during the preceding 5 years (2004-2009); 10.0% of patients were prescribed physical therapy specific to OA, 2.6% received an unloader brace, 0.52% underwent acupuncture, 43.5% were administered intra-articular corticosteroids, and 15.4% received viscosupplementation injections. During the 5 years before arthroplasty, 2,505 patients (19.6%) underwent arthroscopy and debridement/lavage, 35% of whom did not have a diagnosis code for mechanical pathology. Within 1 year of knee arthroplasty, 2,028 of the 2,505 knee arthroscopies (80.9%) were performed. CONCLUSIONS The findings show that significant gaps do exist between the evidence-based American Academy of Orthopaedic Surgeons recommendations and actual practice patterns in the United States between 2004 and 2009. LEVEL OF EVIDENCE Level IV, diagnostic study.

Basic fibroblast growth factor accelerates matrix degradation via a neuro-endocrine pathway in human adult articular chondrocytes

Pain‐related neuropeptides released from synovial fibroblasts, such as substance P, have been implicated in joint destruction. Substance P‐induced inflammatory processes are mediated via signaling through a G‐protein‐coupled receptor, that is, neurokinin‐1 tachykinin receptor (NK1‐R). We determined the pathophysiological link between substance P and its receptor in human adult articular cartilage homeostasis. We further examined if catabolic growth factors such as basic fibroblast growth factor (bFGF or FGF‐2) or IL‐1β accelerate matrix degradation via a neural pathway upregulation of substance P and NK1‐R. We show here that substance P stimulates the production of cartilage‐degrading enzymes, such as matrix metalloproteinase‐13 (MMP‐13), and suppresses proteoglycan deposition in human adult articular chondrocytes via NK1‐R. Furthermore, we have demonstrated that substance P negates proteoglycan stimulation promoted by bone morphogenetic protein‐7, suggesting the dual role of substance P as both a pro‐catabolic and anti‐anabolic mediator of cartilage homeostasis. We report that bFGF‐mediated stimulation of substance P and its receptor NK1‐R is, in part, through an IL‐1β‐dependent pathway. J. Cell. Physiol. 215: 452–463, 2008.

The Action of Resveratrol, a Phytoestrogen Found in Grapes, on the Intervertebral Disc

Study Design. Basic science, biologic study. Objective. To determine the potential benefits of using resveratrol (RSV) for intervertebral disc (IVD) matrix repair and regeneration. Summary of Background Data. The phytoestrogen RSV is a natural compound found in various plants including grapes and red wines. RSV has been reported to provide a protective effect on articular cartilage in rabbit models for arthritis, but its effect on spine cartilage is unknown. Methods. We studied the effect of RSV on bovine IVD cartilage homeostasis by assessing MMP-13 (potent catabolic factor) production, proteoglycan (PG) accumulation and synthesis, and the interaction between RSV and known catabolic factors such as bFGF or IL-1. To understand the molecular mechanisms by which RSV modulates MMP-13 and PG production, we also investigated its downstream target regulatory molecules. Results. Stimulation of bovine disc cells cultured in monolayer with bFGF or IL-1 augmented the production of MMP-13 and ADAMTS-4 at the transcriptional level and this augmentation was blocked by RSV. Incubation of nucleus pulposus cells with RSV for 21 days significantly increased PG accumulation per cell in a dose-dependent manner, increased PG synthesis, rescued PG losses induced by catabolic reagents bFGF and IL-1, and promoted cell survival to levels seen after incubation with the anabolic protein BMP7 100 ng/mL. Protein-DNA interaction array results suggest that RSV effectively suppresses downstream target molecules of bFGF and IL-1 responsible for oxidative stress, proliferation, and apoptosis. Conclusion. Resveratrol is a potent anabolic mediator of bovine IVD cartilage homeostasis, revealing its potential as a unique biologic treatment to slow the progression of IVD degeneration. These data suggests RSV may have considerable promise in the treatment of disc degeneration.