Clinical potential and challenges of using genetically modified cells for articular cartilage repair

Articular cartilage defects do not regenerate. Transplantation of autologous articular chondrocytes, which is clinically being performed since several decades, laid the foundation for the transplantation of genetically modified cells, which may serve the dual role of providing a cell population capable of chondrogenesis and an additional stimulus for targeted articular cartilage repair. Experimental data generated so far have shown that genetically modified articular chondrocytes and mesenchymal stem cells (MSC) allow for sustained transgene expression when transplanted into articular cartilage defects in vivo. Overexpression of therapeutic factors enhances the structural features of the cartilaginous repair tissue. Combined overexpression of genes with complementary mechanisms of action is also feasible, holding promises for further enhancement of articular cartilage repair. Significant benefits have been also observed in preclinical animal models that are, in principle, more appropriate to the clinical situation. Finally, there is convincing proof of concept based on a phase I clinical gene therapy study in which transduced fibroblasts were injected into the metacarpophalangeal joints of patients without adverse events. To realize the full clinical potential of this approach, issues that need to be addressed include its safety, the choice of the ideal gene vector system allowing for a long-term transgene expression, the identification of the optimal therapeutic gene(s), the transplantation without or with supportive biomaterials, and the establishment of the optimal dose of modified cells. As safe techniques for generating genetically engineered articular chondrocytes and MSCs are available, they may eventually represent new avenues for improved cell-based therapies for articular cartilage repair. This, in turn, may provide an important step toward the unanswered question of articular cartilage regeneration

Cyst formation in the subchondral bone following cartilage repair

Subchondral bone cysts represent an early postoperative sign associated with many articular cartilage repair procedures. They may be defined as an abnormal cavity within the subchondral bone in close proximity of a treated cartilage defect with a possible communication to the joint cavity in the absence of osteoarthritis. Two synergistic mechanisms of subchondral cyst formation, the theory of internal upregulation of local proinflammatory factors, and the external hydraulic theory, are proposed to explain their occurrence. This review describes subchondral bone cysts in the context of articular cartilage repair to improve investigations of these pathological changes. It summarizes their epidemiology in both preclinical and clinical settings with a focus on individual cartilage repair procedures, examines an algorithm for subchondral bone analysis, elaborates on the underlying mechanism of subchondral cyst formation, and condenses the clinical implications and perspectives on subchondral bone cyst formation in cartilage repair

Osteoarthritis: Novel Molecular Mechanisms Increase Our Understanding of the Disease Pathology

Although osteoarthritis (OA) is the most common musculoskeletal condition that causes significant health and social problems worldwide, its exact etiology is still unclear. With an aging and increasingly obese population, OA is becoming even more prevalent than in previous decades. Up to 35% of the world’s population over 60 years of age suffers from symptomatic (painful, disabling) OA. The disease poses a tremendous economic burden on the health-care system and society for diagnosis, treatment, sick leave, rehabilitation, and early retirement. Most patients also experience sleep disturbances, reduced capability for exercising, lifting, and walking and are less capable of working, and maintaining an independent lifestyle. For patients, the major problem is disability, resulting from joint tissue destruction and pain. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects. Here, we elucidate novel concepts and hypotheses regarding disease progression and pathology, which are relevant for understanding underlying the molecular mechanisms as a prerequisite for future therapeutic approaches. Emphasis is placed on topographical modeling of the disease, the role of proteases and cytokines in OA, and the impact of the peripheral nervous system and its neuropeptides

Mitochondrial Genome Editing to Treat Human Osteoarthritis—A Narrative Review

Osteoarthritis (OA) is a severe, common chronic orthopaedic disorder characterised by a degradation of the articular cartilage with an incidence that increases over years. Despite the availability of various clinical options, none can stop the irreversible progression of the disease to definitely cure OA. Various mutations have been evidenced in the mitochondrial DNA (mtDNA) of cartilage cells (chondrocytes) in OA, leading to a dysfunction of the mitochondrial oxidative phos phorylation processes that significantly contributes to OA cartilage degeneration. The mitochondrial genome, therefore, represents a central, attractive target for therapy in OA, especially using genome editing procedures. In this narrative review article, we present and discuss the current advances and breakthroughs in mitochondrial genome editing as a potential, novel treatment to overcome mtDNA-related disorders such as OA. While still in its infancy and despite a number of challenges that need to be addressed (barriers to effective and site-specific mtDNA editing and repair), such a strategy has strong value to treat human OA in the future, especially using the groundbreaking clus tered regularly interspaced short palindromic repeats (CRIPSR)/CRISPR-associated 9 (CRISPR/Cas9) technology and mitochondrial transplantation approaches

Application of Alginate Hydrogels for Next-Generation Articular Cartilage Regeneration

The articular cartilage has insufficient intrinsic healing abilities, and articular cartilage injuries often progress to osteoarthritis. Alginate-based scaffolds are attractive biomaterials for cartilage repair and regeneration, allowing for the delivery of cells and therapeutic drugs and gene sequences. In light of the heterogeneity of findings reporting the benefits of using alginate for cartilage regeneration, a better understanding of alginate-based systems is needed in order to improve the approaches aiming to enhance cartilage regeneration with this compound. This review provides an in-depth evaluation of the literature, focusing on the manipulation of alginate as a tool to support the processes involved in cartilage healing in order to demonstrate how such a material, used as a direct compound or combined with cell and gene therapy and with scaffold-guided gene transfer procedures, may assist cartilage regeneration in an optimal manner for future applications in patients

Subchondral bone remodeling patterns in larger animal models of meniscal injuries inducing knee osteoarthritis - a systematic review

Purpose Elucidating subchondral bone remodeling in preclinical models of traumatic meniscus injury may address clinically relevant questions about determinants of knee osteoarthritis (OA). Methods Studies on subchondral bone remodeling in larger animal models applying meniscal injuries as standardizing entity were systematically analyzed. Of the identifed 5367 papers reporting total or partial meniscectomy, meniscal transection or destabilization, 0.4% (in guinea pigs, rabbits, dogs, minipigs, sheep) remained eligible. Results Only early or mid-term time points were available. Larger joint sizes allow reporting higher topographical details. The most frequently reported parameters were BV/TV (61%), BMD (41%), osteophytes (41%) and subchondral bone plate thickness (39%). Subchondral bone plate microstructure is not comprehensively, subarticular spongiosa microstructure is well characterized. The subarticular spongiosa is altered shortly before the subchondral bone plate. These early changes involve degradation of subarticular trabecular elements, reduction of their number, loss of bone volume and reduced mineralization. Soon thereafter, the previously normal subchondral bone plate becomes thicker. Its porosity frst increases, then decreases. Conclusion The specifc human topographical pattern of a thinner subchondral bone plate in the region below both menisci is present solely in the larger species (partly in rabbits), but absent in rodents, an important fact to consider when designing animal studies examining subchondral consequences of meniscus damage. Large animal models are capable of providing high topographical detail, suggesting that they may represent suitable study systems refecting the clinical complexities. For advanced OA, signifcant gaps of knowledge exist. Future investigations assessing the subchondral bone in a standardized fashion are warranted

Joint Cartilage in Long-Duration Spaceflight

This review summarizes the current literature available on joint cartilage alterations in long-duration spaceflight. Evidence from spaceflight participants is currently limited to serum biomarker data in only a few astronauts. Findings from analogue model research, such as bed rest studies, as well as data from animal and cell research in real microgravity indicate that unloading and radiation exposure are associated with joint degeneration in terms of cartilage thinning and changes in cartilage composition. It is currently unknown how much the individual cartilage regions in the different joints of the human body will be affected on long-term missions beyond the Low Earth Orbit. Given the fact that, apart from total joint replacement or joint resurfacing, currently no treatment exists for late-stage osteoarthritis, countermeasures might be needed to avoid cartilage damage during long-duration missions. To plan countermeasures, it is important to know if and how joint cartilage and the adjacent structures, such as the subchondral bone, are affected by long-term unloading, reloading, and radiation. The use of countermeasures that put either load and shear, or other stimuli on the joints, shields them from radiation or helps by supporting cartilage physiology, or by removing oxidative stress possibly help to avoid OA in later life following long-duration space missions. There is a high demand for research on the efficacy of such countermeasures to judge their suitability for their implementation in long-duration missions

Gentherapie in der Orthopädie

Gentherapie in der Orthopädie wird intensiv im Rahmen verschiedener vererbbarer und nichtvererbbarer orthopädischer Krankheiten untersucht. Der experimentelle Fortschritt auf diesem Gebiet ist durch die Komplexität von Vektorauswahl und -herstellung, Gentransfertechnik, Applikationsweg in geeigneten Tier-Modellen sowie dem Nachweis auf struktureller und funktioneller Ebene gekennzeichnet. Die ersten klinischen Studien zur Gentherapie der chronischen Polyarthritis haben bereits ihre praktische Durchführbarkeit demonstriert. Es ist wahrscheinlich, dass genbasierte Verfahren zur Erweiterung und Verbesserung bestehender orthopädisch-chirurgischer Therapien führen werden. Schlüsselwörter Gentherapie · Gentransfer · Orthopädie · Klinische Studie

Enhanced expression of the central survival of motor neuron (SMN) protein during the pathogenesis of osteoarthritis

The identification of new components implicated in the pathogenesis of osteoarthritis (OA) might improve our understanding of the disease process. Here, we investigated the levels of the survival of motor neuron (SMN) expression in OA cartilage considering the fundamental role of the SMN protein in cell survival and its involvement in other stress-associated pathologies. We report that SMN expression is up-regulated in human OA compared with normal cartilage, showing a strong correlation with the disease severity, a result confirmed in vivo in an experimental model of the disease. We further show that the prominent inflammatory cytokines (IL-1β, TNF-α) are critical inducers of SMN expression. This is in marked contrast with the reported impaired levels of SMN in spinal muscular atrophy, a single inherited neuromuscular disorder characterized by mutations in the smn gene whereas OA is a complex disease with multiple aetiologies. While the precise functions of SMN during OA remain to be elucidated, the conclusions of this study shed light on a novel pathophysiological pathway involved in the progression of OA, potentially offering new targets for therapy