Reflections from the OARSI 2022 clinical trials symposium: The pain of OA-Deconstruction of pain and patient-reported outcome measures for the benefit of patients and clinical trial design.

OBJECTIVE: Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field. METHOD: The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development. RESULTS: Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions. CONCLUSIONS: The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.

Reflections from the 2021 OARSI clinical trial symposium: Considerations for understanding biomarker assessments in osteoarthritis drug development - Should future studies focus on disease activity, rather than status?

Objective: Osteoarthritis (OA) is heterogeneous disease, for which drug development has proven to be challenging, both facilitated and hampered by changing guidelines. This is evident by the current lack of approved treatments, which improve joint function and delay joint failure. There is a need to bring together key stakeholders to discuss, align and enhance the processes for OA drug development to benefit patients. Design: To facilitate drug development, the Osteoarthritis Research Society International (OARSI) initiated a series of annual clinical trials symposia (CTS). The aim of these symposia was to bring together academics, translational and clinical scientists, regulators, drug developers, and patient advocacy groups to share, refine and enhance the drug development process for the benefit of patients. Results: OARSI is now considered the leading organization to facilitate open dialogue between all these stakeholders, in the intersection of understanding of the pathologies and drug development. Clearly, such a pivotal task needs an annual forum to allow stakeholders to share and discuss information, as possible solutions are joint efforts rather than a single stakeholder contribution. Conclusions: The main topic of the 2021 CTS was how to improve clinical studies to help patients through overcoming barriers to development of new disease modifying treatments for OA. One key aspect was the focus on definitions of disease activity, status and the definitions of "illness vs disease". There is a clear medical need to couple a given disease activity with the optimal intervention for the right patient.

The association of the lipid profile with knee and hand osteoarthritis severity: the IMI-APPROACH cohort.

OBJECTIVE: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. DESIGN: We used baseline data from the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons with knee OA fulfilling the clinical American College of Rheumatology classification criteria. Radiographic knee and hand OA severity was quantified with Kellgren-Lawrence sum scores. Knee and hand pain and function were assessed with validated questionnaires. We quantified fasted plasma higher order lipids and oxylipins with liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based platforms. Using penalised linear regression, we assessed the variance in OA severity explained by lipidomics, with adjustment for clinical covariates (age, sex, body mass index (BMI) and lipid lowering medication), measurement batch and clinical centre. RESULTS: In 216 participants (mean age 66 years, mean BMI 27.3 kg/m2, 75% women) we quantified 603 higher order lipids (triacylglycerols, diacylglycerols, cholesteryl esters, ceramides, free fatty acids, sphingomyelins, phospholipids) and 28 oxylipins. Lipidomics explained 3% and 2% of the variance in radiographic knee and hand OA severity, respectively. Lipids were not associated with knee pain or function. Lipidomics accounted for 12% and 6% of variance in hand pain and function, respectively. The investigated OA severity outcomes were associated with the lipidomic fraction of bound and free arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid and docosapentaenoic acid. CONCLUSIONS: Within the APPROACH cohort lipidomics explained a minor portion of the variation in OA severity, which was most evident for the outcome hand pain. Our results suggest that eicosanoids may be involved in OA severity.

Combining segmental bulk- and single-cell RNA-sequencing to define the chondrocyte gene expression signature in the murine knee joint.

OBJECTIVE: Due to the small size of the murine knee joint, extracting the chondrocyte transcriptome from articular cartilage (AC) is a major technical challenge. In this study, we demonstrate a new pragmatic approach of combining bulk RNA-sequencing (RNA-seq) and single cell (sc)RNA-seq to address this problem. DESIGN: We propose a new cutting strategy for the murine femur which produces three segments with a predictable mixed cell population, where one segment contains AC and growth plate (GP) chondrocytes, another GP chondrocytes, and the last segment only bone and bone marrow. We analysed the bulk RNA-seq of the different segments to find distinct genes between the segments. The segment containing AC chondrocytes was digested and analysed via scRNA-seq. RESULTS: Differential expression analysis using bulk RNA-seq identified 350 candidate chondrocyte gene in the AC segment. Gene set enrichment analysis of these genes revealed biological processes related- and non-related to chondrocytes, including, cartilage development (adj. P-value: 3.45E-17) and endochondral bone growth (adj. P-value 1.22E-4), respectively. ScRNA-seq of the AC segment found a cluster of 131 cells containing mainly chondrocytes. This cluster had 759 differentially expressed genes which enriched for extracellular matrix organisation (adj. P-value 7.76E-40) and other joint development processes. The intersection of the gene sets of bulk- and scRNA-seq contained 75 genes. CONCLUSIONS: Based on our results, we conclude that the combination of the two RNA-seq methods is necessary to precisely delineate the chondrocyte transcriptome and to study the disease phenotypes of chondrocytes in murine OA models in the future.

Design and development of poly-L/D-lactide copolymer and barium titanate nanoparticle 3D composite scaffolds using breath figure method for tissue engineering applications.

In tissue engineering, the scaffold topography influences the adhesion, proliferation, and function of cells. Specifically, the interconnected porosity is crucial for cell migration and nutrient delivery in 3D scaffolds. The objective of this study was to develop a 3D porous composite scaffold for musculoskeletal tissue engineering applications by incorporating barium titanate nanoparticles (BTNPs) into a poly-L/D-lactide copolymer (PLDLA) scaffold using the breath figure method. The porous scaffold fabrication utilised 96/04 PLDLA, dioleoyl phosphatidylethanolamine (DOPE), and different types of BTNPs, including uncoated BTNPs, Al2O3-coated BTNPs, and SiO2-coated BTNPs. The BTNPs were incorporated into the polymer scaffold, which was subsequently analysed using field emission scanning electron microscopy (FE-SEM). The biocompatibility of each scaffold was tested using ovine bone marrow stromal stem cells. The cell morphology, viability, and proliferation were evaluated using FE-SEM, LIVE/DEAD staining, and Prestoblue assay. Porous 3D composite scaffolds were successfully produced, and it was observed that the incorporation of uncoated BTNPs increased the average pore size from 1.6 µm (PLDLA) to 16.2 µm (PLDLA/BTNP). The increased pore size in the PLDLA/BTNP scaffolds provided a suitable porosity for the cells to migrate inside the scaffold, while in the pure PLDLA scaffolds with their much smaller pore size, cells elongated on the surface. To conclude, the breath figure method was successfully used to develop a PLDLA/BTNP scaffold. The use of uncoated BTNPs resulted in a composite scaffold with an optimal pore size while maintaining the honeycomb-like structure. The composite scaffolds were biocompatible and yielded promising structures for future tissue engineering applications.

Biomatrices for Heart Regeneration and Cardiac Tissue Modelling In Vitro.

Cardiac muscle is the hardest working muscle in the body, pumping approximately 70 g of blood with every heartbeat, circulating 9500 l of blood daily and contracting over 3 billion times during the average human's life. Heart failure - a heterogeneous syndrome - is a major and increasing health care problem worldwide and a leading cause of hospitalization and morbidity in elderly. Adequate heart tissue regeneration in human is lacking. Challenges to engineer heart tissue and employ it in vitro or in regenerative medicine remain to be solved. First of all, cardiac tissue bioengineering requires robust and powerful cells capable of differentiating into cardiomyogenic lineages in combination with effective, safe and highly specialized biomaterials, hydrogels and/or scaffolds for recreating the native extracellular microenvironment. Advances in stem cell and biomaterial science already provided an increasing array of cell resources, their cultivation technologies and biomatrices for efficient and safe cardiac tissue reconstruction. In order to develop new cardiac tissue mimicking technologies in vitro, it is necessary to analyze the advantages and drawbacks of already established biosystems. Therefore, in this paper, we provide a comprehensive overview of recently employed cells, 2D and 3D biomatrices for cardiac tissue engineering and review the current state-of-the-art in this field as well as future directions.

A consensus-based framework for conducting and reporting osteoarthritis phenotype research.

BACKGROUND: The concept of osteoarthritis (OA) heterogeneity is evolving and gaining renewed interest. According to this concept, distinct subtypes of OA need to be defined that will likely require recognition in research design and different approaches to clinical management. Although seemingly plausible, a wide range of views exist on how best to operationalize this concept. The current project aimed to provide consensus-based definitions and recommendations that together create a framework for conducting and reporting OA phenotype research. METHODS: A panel of 25 members with expertise in OA phenotype research was composed. First, panel members participated in an online Delphi exercise to provide a number of basic definitions and statements relating to OA phenotypes and OA phenotype research. Second, panel members provided input on a set of recommendations for reporting on OA phenotype studies. RESULTS: Four Delphi rounds were required to achieve sufficient agreement on 11 definitions and statements. OA phenotypes were defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Reporting recommendations pertaining to the study characteristics, study population, data collection, statistical analysis, and appraisal of OA phenotype studies were provided. CONCLUSIONS: This study provides a number of consensus-based definitions and recommendations relating to OA phenotypes. The resulting framework is intended to facilitate research on OA phenotypes and increase combined efforts to develop effective OA phenotype classification. Success in this endeavor will hopefully translate into more effective, differentiated OA management that will benefit a multitude of OA patients.

Aggrecanase degradation of type III collagen is associated with clinical knee pain.

There is a lack of biochemical markers for non-invasive and objective assessment of symptomatic osteoarthritis (OA). Aggrecanase activity has been shown to be associated with joint deterioration and symptomatic disease through the degradation of extracellular matrix proteins, such as type III collagen. Our study aimed to identify and develop a novel biomarker by measuring an aggrecanase-mediated type III collagen neoepitope, and correlate levels of this biomarker with OA joint pain. Mass spectrometric analysis of purified type III collagen, degraded by the aggrecanase A Disintigrin and Metalloproteinase with Thrombospondin motif (ADAMTS), revealed a fragment generated by ADAMTS-1, -4 and -8. A monoclonal antibody was raised against the neoepitope of this fragment (COL3-ADAMTS) and a competitive ELISA was developed and tested; using serum samples from a cross-sectional cohort of patients with different degrees of knee OA (n = 261). The COL3/ADAMTS ELISA was technically robust and specific for the ADAMTS-1, -4 and -8 generated neoepitope. COL3/ADAMTS was released form cytokine stimulated synovial cultures, indicating a biologic link between the marker and synovium. In OA patients, serum COL3/ADAMTS was independently associated with pain scores (rho = -0.13-0.17, p < 0.05). This association was associated significantly with the presence of radiographic OA. Together, these data indicate that COL3/ADAMTS could be a marker of early osteoarthritis and the underlining pathology.

The Potential of Menstrual Blood-Derived Mesenchymal Stem Cells for Cartilage Repair and Regeneration: Novel Aspects.

Menstrual blood is a unique body fluid that contains mesenchymal stem cells (MSCs). These cells have attracted a great deal of attention due to their exceptional advantages including easy access and frequently accessible sample source and no need for complex ethical and surgical interventions, as compared to other tissues. Menstrual blood-derived MSCs possess all the major stem cell properties and even have a greater proliferation and differentiation potential as compared to bone marrow-derived MSCs, making them a perspective tool in a further clinical practice. Although the potential of menstrual blood stem cells to differentiate into a large variety of tissue cells has been studied in many studies, their chondrogenic properties have not been extensively explored and investigated. Articular cartilage is susceptible to traumas and degenerative diseases, such as osteoarthritis, and has poor self-regeneration capacity and therefore requires more effective therapeutic technique. MSCs seem promising candidates for cartilage regeneration; however, no clinically effective stem cell-based repair method has yet emerged. This chapter focuses on studies in the field of menstrual blood-derived MSCs and their chondrogenic differentiation potential and suitability for application in cartilage regeneration. Although a very limited number of studies have been made in this field thus far, these cells might emerge as an efficient and easily accessible source of multipotent cells for cartilage engineering and cell-based chondroprotective therapy.

Chondrocyte secretome: a source of novel insights and exploratory biomarkers of osteoarthritis.

The extracellular matrix (ECM) of articular cartilage is comprised of complex networks of proteins and glycoproteins, all of which are expressed by its resident cell, the chondrocyte. Cartilage is a unique tissue given its complexity and ability to resist repeated load and deformation. The mechanisms by which articular cartilage maintains its integrity throughout our lifetime is not fully understood, however there are numerous regulatory pathways known to govern ECM turnover in response to mechanical stimuli. To further our understanding of this field, we envision that proteomic analysis of the secretome will provide information on how the chondrocyte remodels the surrounding ECM in response to load, in addition to providing information on the metabolic state of the cell. In this review, we attempt to summarize the recent mass spectrometry-based proteomic discoveries in healthy and diseased cartilage and chondrocytes, to facilitate the discovery of novel biomarkers linked to degenerative pathologies, such as osteoarthritis (OA).

Osteoarthritis Year in Review 2016: biomarkers (biochemical markers).

PURPOSE: The aim of this "Year in Review" article is to summarize and discuss the implications of biochemical marker related articles published between the Osteoarthritis Research Society International (OARSI) 2015 Congress in Seattle and the OARSI 2016 Congress in Amsterdam. METHODS: The PubMed/MEDLINE bibliographic database was searched using the combined keywords: 'biomarker' and 'osteoarthritis'. The PubMed/MEDLINE literature search was conducted using the Advanced Search Builder function (http://www.ncbi.nlm.nih.gov/pubmed/advanced). RESULTS: Over two hundred new biomarker-related papers were published during the literature search period. Some papers identified new biomarkers whereas others explored the biological properties and clinical utility of existing markers. There were specific references to several adipocytokines including leptin and adiponectin. ADAM Metallopeptidase with Thrombospondin Type 1 motif 4 (ADAMTS-4) and aggrecan ARGS neo-epitope fragment (ARGS) in synovial fluid (SF) and plasma chemokine (CeC motif) ligand 3 (CCL3) were reported as potential new knee biomarkers. New and refined proteomic technologies and novel assays including a fluoro-microbead guiding chip (FMGC) for measuring C-telopeptide of type II collagen (CTX-II) in serum and urine and a novel magnetic nanoparticle-based technology (termed magnetic capture) for collecting and concentrating CTX-II, were described this past year. CONCLUSION: There has been steady progress in osteoarthritis (OA) biomarker research in 2016. Several novel biomarkers were identified and new technologies have been developed for measuring existing biomarkers. However, there has been no "quantum leap" this past year and identification of novel early OA biomarkers remains challenging. During the past year, OARSI published a set of recommendations for the use of soluble biomarkers in clinical trials, which is a major step forward in the clinical use of OA biomarkers and bodes well for future OA biomarker development.

Osteoarthritis biomarkers derived from cartilage extracellular matrix: Current status and future perspectives.

Specific soluble biomarkers can be powerful tools for the diagnosis, prognosis and personalized management of osteoarthritis (OA). Biomarkers are potential indicators of the effect of a drug on cartilage metabolism and provide crucial information about the mechanisms of drug action. In this review, we address key questions concerning the use of biomarkers in OA management: Why do we need soluble biomarkers? What are the most widely investigated biomarkers derived from cartilage extracellular matrix? What are the most common pitfalls in interpreting soluble biomarker measurements? What are the perspectives and future research directions in this field? We review current evidence to propose that cartilage-derived soluble biomarkers are complementary "drug development tools" that can be applied during drug development from preclinical research to clinical evaluation. In the future, such biomarkers could be surrogate markers of clinical and/or imaging outcomes. Successful standardization and implementation of automated biomarker assays will facilitate their use in companion diagnostics in the context of personalized medicine for enhanced management of OA.

Altered joint tribology in osteoarthritis: Reduced lubricin synthesis due to the inflammatory process. New horizons for therapeutic approaches.

Osteoarthritis (OA) is the most common form of joint disease. This review aimed to consolidate the current evidence that implicates the inflammatory process in the attenuation of synovial lubrication and joint tissue homeostasis in OA. Moreover, with these findings, we propose some evidence for novel therapeutic strategies for preventing and/or treating this complex disorder. The studies reviewed support that inflammatory mediators participate in the onset and progression of OA after joint injury. The flow of pro-inflammatory cytokines following an acute injury seems to be directly associated with altered lubricating ability in the joint tissue. The latter is associated with reduced level of lubricin, one of the major joint lubricants. Future research should focus on the development of new therapies that attenuate the inflammatory process and restore lubricin synthesis and function. This approach could support joint tribology and synovial lubrication leading to improved joint function and pain relief.

Effect of Prenatal and Neonatal Anti-Androgen Flutamide Treatment on Aquaporin 5 Expression in the Adult Porcine Ovary.

The growth of ovarian follicles is accompanied by fluid-filled antrum formation. Water movement within the follicular wall is predominantly transcellular via membranous water channels named aquaporins (AQPs). Androgens are important regulators of mammalian folliculogenesis, and their prenatal and/or neonatal deficiency affects female fertility in adulthood. Therefore, this study was performed to determine whether gestational or neonatal exposure to the anti-androgen flutamide influences androgen-dependent AQP5 expression in pre-antral and large antral follicles of adult pigs. Flutamide was injected into pregnant gilts between days 80 and 88 of gestation and into female piglets between days 2 and 10 post-natally. The ovaries were collected from flutamide-treated and non-treated (control) sexually mature pigs. In pre-antral follicles, AQP5 mRNA and protein levels were both downregulated following maternal (p < 0.01 and p < 0.01, respectively) and neonatal (p < 0.01 and p < 0.01, respectively) flutamide exposure. Likewise, the expression of mRNA (p < 0.01 and p < 0.001, respectively) and protein (p < 0.05 and p < 0.01, respectively) for AQP5 were diminished in large antral follicles in both groups. Immunohistochemistry showed decreased intensity of AQP5 immunoreaction in pre-antral (p < 0.01) and large antral (p < 0.001) follicles following flutamide treatment. Moreover, radioimmunological analysis revealed that changes observed in AQP5 expression corresponded with diminished follicular androgens production after both maternal (p < 0.05 and p < 0.05, respectively) and neonatal (p < 0.05 and p < 0.01, respectively) flutamide administration. Therefore, AQP5 appears to be a potential regulator of follicular fluid accumulation, under androgen control, and may be a key factor in antral follicle growth.

Osteoarthritis year in review 2015: soluble biomarkers and the BIPED criteria.

OBJECTIVE: To review and summarize biomarker data published from April 2014 to May 2015 to provide insight to the ongoing work in the field of osteoarthritis (OA). Furthermore, to summarize the BIPED criteria and set it in context of the medical needs of 2015. METHODS: PubMed was used as searching machine: Time period 2014/04/01-2015/05/01, MeSH term [Biomarker] AND [Osteoarthritis], Language; English, Full text available. Reviews were excluded. Only papers describing protein based biomarkers measured in human body fluids from OA patients were included. RESULTS: Biomarkers of joint tissue turnover, cytokines, chemokines and peptide arrays were measured in different cohorts and studies. Amongst those were previously tested biomarkers such as osteocalcin, Carboxy-terminal cross-linked fragment of type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP). A majority of the biomarker were classified as I, B or B biomarkers according to the BIPED criteria. Work is continuing on testing biomarkers in OA. There is still a huge, unmet medical need to identify, test, validate and qualify novel and well-known biomarkers. A pre-requisite for this is better characterization and classification of biomarkers to their needs, which may not be reached before higher understanding of OA phenotypes has been gained. In addition, we provide some references to some recent guidelines from Food and Drug Administration (FDA) and European Medicines Agency (EMA) on qualification and usage of biomarkers for drug development and personalized medicine, which may provide value to the field.

Water intake, faecal output and intestinal motility in horses moved from pasture to a stabled management regime with controlled exercise.

REASONS FOR PERFORMING STUDY: A change in management from pasture to stabling is a risk factor for equine colic. OBJECTIVES: To investigate the effect of a management change from pasture with no controlled exercise to stabling with light exercise on aspects of gastrointestinal function related to large colon impaction. The hypothesis was that drinking water intake, faecal output, faecal water content and large intestinal motility would be altered by a transition from a pastured to a stabled regime. STUDY DESIGN: Within-subject management intervention trial involving changes in feeding and exercise using noninvasive techniques. METHODS: Seven normal horses were evaluated in a within-subjects study design. Horses were monitored while at pasture 24 h/day, and for 14 days following a transition to a stabling regime with light controlled exercise. Drinking water intake, faecal output and faecal dry matter were measured. Motility of the caecum, sternal flexure and left colon (contractions/min) were measured twice daily by transcutaneous ultrasound. Mean values were pooled for the pastured regime and used as a reference for comparison with stabled data (Days 1-14 post stabling) for multilevel statistical analysis. RESULTS: Drinking water intake was significantly increased (mean ± s.d. pasture 2.4 ± 1.8 vs. stabled 6.4 ± 0.6 l/100 kg bwt/day), total faecal output was significantly decreased (pasture 4.62 ± 1.69 vs. stabled 1.81 ± 0.5 kg/100 kg bwt/day) and faecal dry matter content was significantly increased (pasture 18.7 ± 2.28 vs. stabled 27.2 ± 1.93% DM/day) on all days post stabling compared with measurements taken at pasture (P<0.05). Motility was significantly decreased in all regions of the large colon collectively on Day 2 post stabling (-0.76 contractions/min), and in the left colon only on Day 4 (-0.62 contractions/min; P<0.05). CONCLUSIONS: There were significant changes in large intestinal motility patterns and parameters relating to gastrointestinal water balance during a transition from pasture to stabled management, particularly during the first 5 days.

Physical activity ameliorates cartilage degeneration in a rat model of aging: a study on lubricin expression.

Osteoarthritis (OA) is a common musculoskeletal disorder characterized by slow progression and joint tissue degeneration. Aging is one of the most prominent risk factors for the development and progression of OA. OA is not, however, an inevitable consequence of aging and age-related changes in the joint can be distinguished from those that are the result of joint injury or inflammatory disease. The question that remains is whether OA can be prevented by undertaking regular physical activity. Would moderate physical activity in the elderly cartilage (and lubricin expression) comparable to a sedentary healthy adult? In this study we used physical exercise in healthy young, adult, and aged rats to evaluate the expression of lubricin as a novel biomarker of chondrocyte senescence. Immunohistochemistry and western blotting were used to evaluate the expression of lubricin in articular cartilage, while enzyme-linked immunosorbent assay was used to quantify lubricin in synovial fluid. Morphological evaluation was done by histology to monitor possible tissue alterations. Our data suggest that moderate physical activity and normal mechanical joint loading in elderly rats improve tribology and lubricative properties of articular cartilage, promoting lubricin synthesis and its elevation in synovial fluid, thus preventing cartilage degradation compared with unexercised adult rats.

The future of osteoarthritis therapeutics: emerging biological therapy.

Biological therapy is a thriving area of research and development, and is well established for chronic forms of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, there is no clinically validated biological therapy for osteoarthritis (OA). Chronic forms of OA are increasingly viewed as an inflammatory disease. OA was largely regarded as a "wear and tear disease". However, the disease is now believed to involve "low grade" inflammation and the growth of blood vessels and nerves from the subchondral bone into articular cartilage. This realization has focused research effort on the development and evaluation of biological therapy that targets proinflammatory mediators, angiogenic factors and cytokines in articular cartilage, subchondral bone and synovium in chronic forms of OA. This review article provides an overview of emerging biological therapy for OA, and discusses recent molecular targets implicated in angiogenesis and neurogenesis and progress with antibody-based therapy, calcitonin, and kartogenin, the small molecule stimulator of chondrogenesis.

The future of osteoarthritis therapeutics: targeted pharmacological therapy.

Osteoarthritis (OA) is one of the most common forms of degenerative joint disease and a major cause of pain and disability affecting the aging population. It is estimated that more than 20 million Americans and 35 to 40 million Europeans suffer from OA. Analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) are the only therapeutic treatment options for OA. Effective pharmacotherapy for OA, capable of restoring the original structure and function of damaged cartilage and other synovial tissue, is urgently needed, and research into such disease-modifying osteoarthritis drugs (DMOADs) is in progress. This is the first of three reviews focusing on OA therapeutics. This paper provides an overview of current research into potential structure-modifying drugs and more appropriately targeted pharmacological therapy. The challenges and opportunities in this area of research and development are reviewed, covering the most up-to-date initiatives, trends, and topics.

Is tendinitis an inflammatory disease initiated and driven by pro-inflammatory cytokines such as interleukin 1ß?

Tendonitis and tendinitis are terms used to describe an inflamed and painful tendon. Tendinopathy, is a descriptive term for describing clinical conditions arising from tendon injury and overuse both within and around tendons. The aim of this mini-review is to explore the role of pro-inflammatory cytokines, particularly interleukin-1ß (IL-1ß) in tendon disorders. A number of investigators including our group have proposed that pro-inflammatory cytokines such as IL-1ß are initiators of tendinopathies, stimulating inflammation, apoptosis and extracellular matrix (ECM) degradation. This is one of the reasons why IL-1ß is frequently used in culture models of tendon inflammation to study the inflammatory and catabolic responses of tenocytes. However, some researchers oppose this view and suggest that although IL-1ß may play a role in rheumatoid arthritis (RA) and osteoarthritis (OA), the involvement of IL-1ß in the development of tendinopathy is questionable. This mini-review discusses the relevant papers published in this area and summarises the evidence for and against the involvement of pro-inflammatory cytokines such as IL-1ß in tendonitis. Reaching a consensus will be important for the development and refinement of biomimetic models of tendon inflammation and the formulation of new therapeutic strategies for the treatment of tendon injuries.