Articular cartilage changes in maturing athletes: new targets for joint rejuvenation.
2014; 6 (1): 18-30
Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis.
Arthritis & rheumatology (Hoboken, N.J.)
2014; 66 (1): 101-106
Articular cartilage has a unique functional architecture capable of providing a lifetime of pain-free joint motion. This tissue, however, undergoes substantial age-related physiologic, mechanical, biochemical, and functional changes that reduce its ability to overcome the effects of mechanical stress and injury. Many factors affect joint function in the maturing athlete-from chondrocyte survival and metabolism to structural composition and genetic/epigenetic factors governing cartilage and synovium. An evaluation of age-related changes for joint homeostasis and risk for osteoarthritis is important to the development of new strategies to rejuvenate aging joints.This review summarizes the current literature on the biochemical, cellular, and physiologic changes occurring in aging articular cartilage.PubMed (1969-2013) and published books in sports health, cartilage biology, and aging.Keywords included aging, athlete, articular cartilage, epigenetics, and functional performance with age.Systematic review.Level 3.To be included, research questions addressed the effect of age-related changes on performance, articular cartilage biology, molecular mechanism, and morphology.The mature athlete faces challenges in maintaining cartilage health and joint function due to age-related changes to articular cartilage biology, morphology, and physiology. These changes include chondrocyte loss and a decline in metabolic response, alterations to matrix and synovial tissue composition, and dysregulation of reparative responses.Although physical decline has been regarded as a normal part of aging, many individuals maintain overall fitness and enjoy targeted improvement to their athletic capacity throughout life. Healthy articular cartilage and joints are needed to maintain athletic performance and general activities. Genetic and potentially reversible epigenetic factors influence cartilage physiology and its response to mechanical and injurious stimuli. Improved understandings of the physical and molecular changes to articular cartilage with aging are important to develop successful strategies for joint rejuvenation.
View details for DOI 10.1177/1941738113514369
View details for PubMedID 24427438
Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints
HUMAN GENE THERAPY
2013; 24 (4): 457-466
We previously demonstrated that carboxypeptidase B (CPB) protects against joint erosion in rheumatoid arthritis by inactivating complement component C5a. We also found that levels of CPB are abnormally high in the synovial fluid of individuals with another joint disease, osteoarthritis (OA). We undertook this study to investigate whether CPB plays a role in the pathogenesis of OA.We compared the development of OA in CPB-deficient (Cpb2(-/-) ) mice and wild-type mice by subjecting them to medial meniscectomy and histologically assessing cartilage damage, osteophyte formation, and synovitis in the stifle joints 4 months later. We measured levels of proCPB, proinflammatory cytokines, and complement components in synovial fluid samples from patients with symptomatic and radiographic knee OA. Finally, we used enzyme-linked immunosorbent assay, flow cytometry, and hemolytic assays to assess the effect of CPB on formation of membrane attack complex (MAC)-a complement effector critical to OA pathogenesis.Cpb2(-/-) mice developed dramatically greater cartilage damage than did wild-type mice (P < 0.01) and had a greater number of osteophytes (P < 0.05) and a greater degree of synovitis (P < 0.05). In synovial fluid samples from OA patients, high levels of proCPB were associated with high levels of proinflammatory cytokines and complement components, and levels of proCPB correlated positively with those of MAC. In in vitro complement activation assays, activated CPB suppressed the formation of MAC as well as MAC-induced hemolysis.Our data suggest that CPB protects against inflammatory destruction of the joints in OA, at least in part by inhibiting complement activation.
View details for DOI 10.1002/art.38213
View details for PubMedID 24449579
A single intra-articular injection of adeno-associated virus (AAV) results in stable and controllable transgene expression in normal rat knees. Because undamaged joints are unlikely to require treatment, the study of AAV delivery in joint injury models is crucial to potential therapeutic applications. This study tests the hypotheses that persistent and controllable AAV-transgene expression are (1) highly localized to the cartilage when AAV is injected postinjury and (2) localized to the intra-articular soft tissues when AAV is injected preinjury. Two AAV injection time points, postinjury and preinjury, were investigated in osteochondral defect and anterior cruciate ligament transection models of joint injury. Rats injected with AAV tetracycline response element (TRE)-luciferase received oral doxycycline for 7 days. Luciferase expression was evaluated longitudinally for 6 months. Transgene expression was persistent and controllable with oral doxycycline for 6 months in all groups. However, the location of transgene expression was different: postinjury AAV-injected knees had luciferase expression highly localized to the cartilage, while preinjury AAV-injected knees had more widespread signal from intra-articular soft tissues. The differential transgene localization between preinjury and postinjury injection can be used to optimize treatment strategies. Highly localized postinjury injection appears advantageous for treatments targeting repair cells. The more generalized and controllable reservoir of transgene expression following AAV injection before anterior cruciate ligament transection (ACLT) suggests an intriguing concept for prophylactic delivery of joint protective factors to individuals at high risk for early osteoarthritis (OA). Successful external control of intra-articular transgene expression provides an added margin of safety for these potential clinical applications.
View details for DOI 10.1089/hum.2012.118
View details for Web of Science ID 000317826200010
View details for PubMedID 23496155