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Concept: Cartilage

180

While the predominant function of all tendons is to transfer force from muscle to bone and position the limbs, some tendons additionally function as energy stores, reducing the cost of locomotion. Energy storing tendons experience extremely high strains and need to be able to recoil efficiently for maximum energy storage and return. In the equine forelimb, the energy storing superficial digital flexor tendon (SDFT) has much higher failure strains than the positional common digital extensor tendon (CDET). However, we have previously shown that this is not due to differences in the properties of the SDFT and CDET fascicles (the largest tendon subunits). Instead, there is a greater capacity for interfascicular sliding in the SDFT which facilitates the greater extensions in this particular tendon (Thorpe et al., 2012). In the current study, we exposed fascicles and interfascicular matrix (IFM) from the SDFT and CDET to cyclic loading followed by a test to failure. The results show that IFM mechanical behaviour is not a result of irreversible deformation, but the IFM is able to withstand cyclic loading, and is more elastic in the SDFT than in the CDET. We also assessed the effect of ageing on IFM properties, demonstrating that the IFM is less able to resist repetitive loading as it ages, becoming stiffer with increasing age in the SDFT. These results provide further indications that the IFM is important for efficient function in energy storing tendons, and age-related alterations to the IFM may compromise function and predispose older tendons to injury.

Concepts: Collagen, Muscle, Cartilage, Tendon

176

Because of its close relationship to tetrapods, Eusthenopteron is an important taxon for understanding the establishment of the tetrapod body plan. Notably, it is one of the earliest sarcopterygians in which the humerus of the pectoral fin skeleton is preserved. The microanatomical and histological organization of this humerus provides important data for understanding the evolutionary steps that built up the distinctive architecture of tetrapod limb bones. Previous histological studies showed that Eusthenopteron’s long-bone organization was established through typical tetrapod ossification modalities. Based on a three-dimensional reconstruction of the inner microstructure of Eusthenopteron’s humerus, obtained from propagation phase-contrast X-ray synchrotron microtomography, we are now able to show that, despite ossification mechanisms and growth patterns similar to those of tetrapods, it also retains plesiomorphic characters such as a large medullary cavity, partly resulting from the perichondral ossification around a large cartilaginous bud as in actinopterygians. It also exhibits a distinctive tubular organization of bone-marrow processes. The connection between these processes and epiphyseal structures highlights their close functional relationship, suggesting that either bone marrow played a crucial role in the long-bone elongation processes or that trabecular bone resulting from the erosion of hypertrophied cartilage created a microenvironment for haematopoietic stem cell niches.

Concepts: Bone, Bone marrow, Skeletal system, Cartilage, Bird, Tetrapod, Long bone, Ichthyostega

169

Articular cartilage maturation is the postnatal development process that adapts joint surfaces to their site-specific biomechanical demands. Maturation involves gross morphological changes that occur through a process of synchronised growth and resorption of cartilage and generally ends at sexual maturity. The inability to induce maturation in biomaterial constructs designed for cartilage repair has been cited as a major cause for their failure in producing persistent cell-based repair of joint lesions. The combination of growth factors FGF2 and TGFβ1 induces accelerated articular cartilage maturation in vitro such that many molecular and morphological characteristics of tissue maturation are observable. We hypothesised that experimental growth factor-induced maturation of immature cartilage would result in a biophysical and biochemical composition consistent with a mature phenotype. Using native immature and mature cartilage as reference, we observed that growth factor-treated immature cartilages displayed increased nano-compressive stiffness, decreased surface adhesion, decreased water content, increased collagen content and smoother surfaces, correlating with a convergence to the mature cartilage phenotype. Furthermore, increased gene expression of surface structural protein collagen type I in growth factor-treated explants compared to reference cartilages demonstrates that they are still in the dynamic phase of the postnatal developmental transition. These data provide a basis for understanding the regulation of postnatal maturation of articular cartilage and the application of growth factor-induced maturation in vitro and in vivo in order to repair and regenerate cartilage defects.

Concepts: Bone, Gene, Molecular biology, Collagen, Cartilage, Knee, Biochemistry, Articular cartilage repair

169

BACKGROUND: Platelet Rich Plasma (PRP), a blood-derived product rich in growth factors, is a promising treatment for cartilage defects but there is still a lack of clinical evidence. The aim of this study is to show, through a randomized double blind prospective trial, the efficacy of this procedure, by comparing PRP to Hyaluronic Acid (HA) injections for the treatment of knee chondropathy or osteoarthritis (OA). METHODS: 109 patients (55 treated with HA and 54 with PRP) were treated and evaluated at 12 months of follow-up. The patients were enrolled according to the following inclusion criteria: age> 18 years, history of chronic (at least 4 months) pain or swelling of the knee and imaging findings of degenerative changes of the joint (Kellgren-Lawrence Score up to 3). A cycle of 3 weekly injections was administered blindly. All patients were prospectively evaluated before and at 2, 6, and 12 months after the treatment by: IKDC, EQ-VAS, TEGNER, and KOOS scores. Range of motion and knee circumference changes were measured over time. Adverse events and patient satisfaction were also recorded. RESULTS: Only minor adverse events were detected in some patients, such as mild pain and effusion after the injections, in particular in the PRP group, where a significantly higher post-injective pain reaction was observed (p=0.039). At the follow-up evaluations, both groups presented a clinical improvement but the comparison between the two groups showed a not statistically significant difference in all scores evaluated. A trend favorable for the PRP group was only found in patients with low grade articular degeneration (Kellgren-Lawrence score up to 2). CONCLUSIONS: Results suggest that PRP injections offer a significant clinical improvement up to one year of follow-up. However, conversely to what was shown by the current literature, for middle-aged patients with moderate signs of OA, PRP results were not better than those obtained with HA injections, and thus it should not be considered as first line treatment. More promising results are shown for its use in low grade degeneration, but they still have to be confirmed.

Concepts: Clinical trial, Randomized controlled trial, Statistical significance, Cartilage, Knee, Pharmaceutical industry, Clinical research, Adverse event

167

Objective. To study the role of different imaging modalities, ultrasonography, conventional radiography (CR) and CT, in visualization of chondrocalcinosis of the knees in patients with CPDD.Methods. Twenty-five patients (14 males and 11 females) with CPDD were enrolled in the study. Diagnosis was made according to D.J. McCarty classification criteria. All patients had arthritis of the knee and underwent aspiration of SF from the knee and microscopic investigation of SF samples. Diagnosis of CPDD was crystal proven. Three imaging methods were performed in patients: CR, CT and US of the knees.Results. CR of the knee confirmed cartilage calcification (CC) in 13 patients, CT in 18 patients and US in 25 patients. No difference in age or disease duration between patients with CC detected by different imaging methods was found.Conclusion. US appeared to be a helpful tool, possibly better than CR or CT, in revealing CC in patients with CPDD. Informativity of CT and CR in the detection of CC is almost equal.

Concepts: Medical imaging, Cartilage, Osteoarthritis, Knee, Difference

167

OBJECTIVE: The 1-34 amino acid segment of the parathyroid hormone (PTH [1-34]) mediates anabolic effects in chondrocytes and osteocytes. The aim of this study was to investigate whether systemic application of PTH [1-34] improves the repair of non-osteoarthritic, focal osteochondral defects in vivo. DESIGN: Standardized cylindrical osteochondral defects were bilaterally created in the femoral trochlea of rabbits (n = 8). Daily subcutaneous injections of 10 μg PTH [1-34]/kg were given to the treatment group (n = 4) for 6 weeks, controls (n = 4) received saline. Articular cartilage repair was evaluated by macroscopic, biochemical, histological and immunohistochemical analyses. Reconstitution of the subchondral bone was assessed by micro-computed tomography. Effects of PTH [1-34] on synovial membrane, apoptosis, and expression of the PTH receptor (PTH1R) were determined. RESULTS: Systemic PTH [1-34] increased PTH1R expression on both, chondrocytes and osteocytes within the repair tissue. PTH [1-34] ameliorated the macro- and microscopic aspect of the cartilaginous repair tissue. It also enhanced the thickness of the subchondral bone plate and the microarchitecture of the subarticular spongiosa within the defects. No significant correlations were established between these coexistent processes. Apoptotic levels, synovial membrane, biochemical composition of the repair tissue, and type-I/II collagen immunoreactivity remained unaffected. CONCLUSIONS: PTH [1-34] emerges as a promising agent in the treatment of focal osteochondral defects as its systemic administration simultaneously stimulates articular cartilage and subchondral bone repair. Importantly, both time-dependent mechanisms of repair did not correlate significantly at this early time point and need to be followed over prolonged observation periods.

Concepts: Bone, Calcitonin, Collagen, Extracellular matrix, Parathyroid hormone, Cartilage, Autologous chondrocyte implantation, Articular cartilage repair

163

Numerous studies have been completed on glaucoma pathogenesis. However, the potential and controversial interaction between ocular biomechanical properties and the glaucomatous diseases process has received much more attention recently. Previous studies have found that collagen tissues gain mutation change in glaucoma patients. This study was conducted to determine the role of collagen in the biomechanics of glaucoma in humans. Its changes may be the result of mechanical modifications brought on by intraocular pressure (IOP) fluctuations. More importantly, biomechanics and genetic evidence indicate that the mutation of collagen may play a role in the process of glaucoma. Alteration of collagen in the outflow pathway may alter mechanical tissue characteristics and a concomitant increase of aqueous humor outflow resistance and elevation of IOP. The variations of collagen, leading to inter-individual differences in scleral and lamina cribrosa properties, result in different susceptibility of individuals to elevated IOP. Therefore, this study hypothesized that collagen mutations may be an original cause of glaucoma.

Concepts: Bone, Genetics, Mutation, Cartilage, Cornea, Intraocular pressure, Biomechanics, Aqueous humour

151

Untreated articular cartilage defects may lead to chronic joint degeneration and functional disability. In the past decade, several cartilage repair techniques have emerged for the treatment of cartilage lesions. Among these techniques, mosaicplasty was introduced by the senior author into the clinical practice in 1992. This article does not intend to give a review or a comparison of currently existing surgical techniques which aim to repair symptomatic focal defects; however, it focuses on the procedures used in the everyday practice in the authors' institute, namely microfracture, mosaicplasty, autologous chondrocyte implantation (ACI), osteochondral allograft transplantation and biodegradable osteochondral scaffolds. It gives a brief summary of these well-described techniques, summarizes the authors' clinical experience and available data on the clinical outcome, and the rehabilitation protocol following different procedures, with a special emphasis on mosaicplasty.

Concepts: Cartilage, Knee, Organ transplant, Knee cartilage replacement therapy, Autologous chondrocyte implantation, Chondrocyte, Articular cartilage damage, Articular cartilage repair

146

Autologous adipose stromal vascular fractions (SVFs) containing adipose tissue-derived stem cells (ASCs) are currently being used in clinical settings for various orthopedic applications for human patients. Due to its potential capability of regenerating cartilage, bone, and tendons, autologous adipose SVFs are being tried in treating patients with osteoarthritis (OA), chondromalacia, meniscus tear, osteonecrosis of the femoral head, and tendon injuries. Here, we have reviewed available human clinical studies with regard to patient applications of autologous adipose SVF containing ASCs, specifically assessing effectiveness and safety in the field of orthopedic disorders. All studies reviewed in this article presents potential benefits of autologous adipose SVF in various orthopedic applications without any serious side effects.

Concepts: Bone, Clinical trial, Collagen, Extracellular matrix, Effectiveness, Cartilage, Ligament, Tendon

145

Osteoarthritis (OA) is a disease affecting multiple tissues of the joints in the elderly, but most notably articular cartilage. Premature biological aging has been described in this tissue and in blood cells, suggesting a systemic component of premature aging in the pathogenesis of OA. Here, we have explored epigenetic aging in OA at the local (cartilage and bone) and systemic (blood) levels. Two DNA methylation age-measures (DmAM) were used: the multi-tissue age estimator for cartilage and bone; and a blood-specific biomarker for blood. Differences in DmAM between OA patients and controls showed an accelerated aging of 3.7 years in articular cartilage (95% CI = 1.1 to 6.3, P = 0.008) of OA patients. By contrast, no difference in epigenetic aging was observed in bone (0.04 years; 95% CI = -1.8 to 1.9, P = 0.3) and in blood (-0.6 years; 95% CI = -1.5 to 0.3, P = 0.2) between OA patients and controls. Therefore, premature epigenetic aging according to DNA methylation changes was specific of OA cartilage, adding further evidence and insight on premature aging of cartilage as a component of OA pathogenesis that reflects damage and vulnerability.

Concepts: DNA, Bone, Death, Cartilage, DNA methylation, Gerontology, Knee, Ageing