The effects of gamma irradiation on the growth plate have been studied in nineteen rabbits with a 1,000 rads/skin dose. The rabbits were killed after one to ninety days. The growth plates were studied by microscopic examination, thymidine-H3 autoradiography, and fluorescence with radiographic measurement. Changes were already detected after twenty-four hours at the cell mitosis level, which showed the sensitiveness of the chondrocyte itself. The lesions were clearly seen with the optical microscope after seven days, and they were most advanced between the fourteenth and twenty-first day after irradiation. Regeneration of the cartilage began in the fourth week and the histological appearance became normal after seventy days. Fluorescence with tetracycline showed a temporary retardation of growth, with consequent shortening of the affected limb

The medial meniscus was resected from the right knees of twelve young grivet monkeys that were killed at intervals of twenty-one to 252 days after operation. The knees operated upon and the control knees were investigated radiologically and histologically. Degenerative changes occurred in the medial femoral and tibial condyles. At first there was loss of cells from the superficial layer of the articular cartilage, with a marked decrease in the acid mucopolysaccharide content of the matrix. The chondrocytes in the deeper layer of the non-calcified zone proliferated to form clones before finally degenerating. The acellular cartilage showed splitting, and with progress of the degenerative process there was thinning and erosion of the cartilage. Eventually there was complete loss of articular cartilage with thickening and exposure of the subchondral bone. These degenerative changes were confined to a small area of the articular cartilage and had occurred despite regeneration of the meniscus. The rest of the cartilage looked normal. It is concluded that articular cartilage deprived of the protection of a meniscus may undergo arthritic changes

In 16 mature New Zealand white rabbits mesenchymal stem cells were aspirated from the bone marrow, cultured in monolayer and implanted on to a full-thickness osteochondral defect artificially made on the patellar groove of the same rabbit. A further 13 rabbits served as a control group. The rabbits were killed after 14 weeks. Healing of the defect was investigated histologically using haematoxylin and eosin and Safranin-O staining and with immunohistochemical staining for type-II collagen. We also used a reverse transcription-polymerase chain reaction (RT-PCR) to detect mRNA of type-I and type-II collagen. The semiquantitative histological scores were significantly higher in the experimental group than in the control group (p < 0.05). In the experimental group immunohistochemical staining on newly formed cartilage was more intense for type-II collagen in the matrix and RT-PCR from regenerated cartilage detected mRNA for type-II collagen in mature chondrocytes. These findings suggest that repair of cartilage defects can be enhanced by the implantation of cultured mesenchymal stem cells

Biochemical changes in the articular cartilage of the knees of mature dogs, one with natural and four with surgically induced osteoarthritis, have been investigated. The four dogs were killed three, six, nine and forty-eight weeks after division of the right anterior cruciate ligament, the left knees serving as controls. The cartilage of the joints operated on was thicker and more hydrated than the control cartilage; the proteoglycans were more easily extracted and had higher galactosamine/glucosamine molar ratios. The proportion of proteoglycans firmly associated with collagen, and hence not extractable, diminished before fibrillation was demonstrable by indian ink staining of the surface. These biochemical changes were present throughout the entire cartilage of the joints operated on of the dogs killed more than three weeks later, and of the dog with natural osteoarthritis. The results suggest that in response to altered mechanical stresses the chondrocytes synthesise proteoglycans that contain more chondroitin sulphate relative to keratin sulphate than normally, as in immature articular cartilage

Little is known of the effects of synovectomy on articular cartilage. In order to investigate this matter, anterior synovectomy of the knee was performed in thirty-five normal adult rabbits and in thirty-five which were given 25 milligrams of hydrocortisone intramuscularly each week afterwards. The animals were killed at intervals from four to 110 days after synovectomy. Histological examination of the regenerating synovium in both groups showed complete structural and functional regeneration by eighty days in the first group and a delay in regeneration in the steroid group. . 35. Sulphur autoradiographs of the articular cartilage of femoral and tibial condyles revealed surface fibrillation and chondrocyte death in 23 per cent of normal knees after eighty days but only 1·8 per cent of knees of animals receiving hydrocortisone. Thus synovectomy in a healthy joint may have an unfavourable effect on the physiology of cartilage by alteration of synovial composition and hyaluronate content in normal joints. Systemically-administered hydrocortisone may reduce this harmful effect in normal cartilage

Our aim was to evaluate the expression of transcription factors CCAAT/enhancer-binding protein-beta (C/EBP. β. ) and C/EBP-homologous protein (CHOP) in the growth plate. Proximal tibial epiphyseal growth plates from ten 15-day-old Wistar rats were used. Additionally, anti-proliferating cell nuclear antigen (PCNA), anti-5-bromo-2’-deoxyuridine (BrdU) immunostaining, terminal transferase dUTP nick end-labelling (TUNEL) and nucleolar organiser region-associated proteins (AgNOR) techniques were peformed. The histological morphology of the growth plate from C/EBP. β. knock-out mice was also analysed. The normal growth plate showed that C/EBP. β. and CHOP factors are expressed both in the germinative/ upper proliferative and in the lower proliferative zones. Furthermore, BdrU+ and PCNA+ cells were present exclusively in the germinative and proliferative zones, while TUNEL+ and AgNOR+ cells were seen in all three zones of the growth plate. Acellular areas, hypocellularity, the increase in cell death and anomalies in the architecture of the cell columns were observed in the growth plates of C/EBP. β. (−/ −) knockout mice. We suggest that C/EBP. β. and CHOP transcription factors may be key modulators participating in the chondrocyte differentiation process in the growth plate

Objectives

Osteoporosis is a metabolic disease resulting in progressive loss of bone mass as measured by bone mineral density (BMD). Physical exercise has a positive effect on increasing or maintaining BMD in postmenopausal women. The contribution of exercise to the regulation of osteogenesis in osteoblasts remains unclear. We therefore investigated the effect of exercise on osteoblasts in ovariectomized mice.

Aim

Osteoarthritis (OA) is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control the expression of genes and are likely to regulate the OA transcriptome. We performed integrative genomic analyses to define methylation-gene expression relationships in osteoarthritic cartilage.

This systematic review examines the current literature regarding surgical techniques for restoring articular cartilage in the hip, from the older microfracture techniques involving perforation to the subchondral bone, to adaptations of this technique using nanofractures and scaffolds. This review discusses the autologous and allograft transfer systems and the autologous matrix-induced chondrogenesis (AMIC) technique, as well as a summary of the previously discussed techniques, which could become common practice for restoring articular cartilage, thus reducing the need for total hip arthroplasty. Using the British Medical Journal Grading of Recommendations, Assessment, Development and Evaluation (BMJ GRADE) system and Grade system. Comparison of the studies discussed shows that microfracture has the greatest quantity and quality of research, whereas the newer AMIC technique requires more research, but shows promise.

Cite this article: W. E. Hotham, A. Malviya. A systematic review of surgical methods to restore articular cartilage in the hip. Bone Joint Res 2018;7:336–342. DOI: 10.1302/2046-3758.75.BJR-2017-0331.

Lesions within the articular cartilage layer of synovial joints do not heal spontaneously. Some repair cells may appear, but their failure to become established may be related to problems of adhesion to proteoglycan-rich surfaces. We therefore investigated whether controlled enzymatic degradation of surface proteoglycan molecules to a depth of about 1 μm, using chondroitinase ABC, would improve coverage by repair cells. We created superficial lesions (1.0 × 0.2 × 5 mm) in the articular cartilage of mature rabbit knees and treated the surfaces with 1 U/ml of chondroitinase ABC for four minutes. The defects were studied by histomorphometry and electron microscopy at one, three and six months. At one month, untreated lesions were covered to a mean extent of 28% by repair cells; this was enhanced to a mean of 53% after enzyme treatment. By three months, the mean coverage of both control and chondroitinase-ABC-treated defects had diminished dramatically to 0.2% and 13%, respectively, but at six months both untreated and treated lesions had a similar coverage of about 30%, not significantly different from that achieved in untreated knees at one month. These findings suggest that, with time, chondrocytes near the surface of the defect may compensate for the loss of proteoglycans produced by enzyme treatment, thereby restoring the inhibitory properties of the matrix as regards cell adhesion. This supposition was confirmed by electron microscopy. Our results have an important bearing on attempts made to induce healing responses by transplanting chondrogenic cells or by applying growth factors

Objectives

The long head of the biceps (LHB) is often resected in shoulder surgery and could therefore serve as a cell source for tissue engineering approaches in the shoulder. However, whether it represents a suitable cell source for regenerative approaches, both in the inflamed and non-inflamed states, remains unclear. In the present study, inflamed and native human LHBs were comparatively characterized for features of regeneration.

Objectives

The lack of effective treatment for cartilage defects has prompted investigations using tissue engineering techniques for their regeneration and repair. The success of tissue-engineered repair of cartilage may depend on the rapid and efficient adhesion of transplanted cells to a scaffold. Our aim in this study was to repair full-thickness defects in articular cartilage in the weight-bearing area of a porcine model, and to investigate whether the CD44 monoclonal antibody biotin-avidin (CBA) binding technique could provide satisfactory tissue-engineered cartilage.

Objectives

The objectives of this study were: 1) to examine osteophyte formation, subchondral bone advance, and bone marrow lesions (BMLs) in osteoarthritis (OA)-prone Hartley guinea pigs; and 2) to assess the disease-modifying activity of an orally administered phosphocitrate ‘analogue’, Carolinas Molecule-01 (CM-01).

Large bone defects remain a tremendous clinical challenge. There is growing evidence in support of treatment strategies that direct defect repair through an endochondral route, involving a cartilage intermediate. While culture-expanded stem/progenitor cells are being evaluated for this purpose, these cells would compete with endogenous repair cells for limited oxygen and nutrients within ischaemic defects. Alternatively, it may be possible to employ extracellular vesicles (EVs) secreted by culture-expanded cells for overcoming key bottlenecks to endochondral repair, such as defect vascularization, chondrogenesis, and osseous remodelling. While mesenchymal stromal/stem cells are a promising source of therapeutic EVs, other donor cells should also be considered. The efficacy of an EV-based therapeutic will likely depend on the design of companion scaffolds for controlled delivery to specific target cells. Ultimately, the knowledge gained from studies of EVs could one day inform the long-term development of synthetic, engineered nanovesicles. In the meantime, EVs harnessed from in vitro cell culture have near-term promise for use in bone regenerative medicine. This narrative review presents a rationale for using EVs to improve the repair of large bone defects, highlights promising cell sources and likely therapeutic targets for directing repair through an endochondral pathway, and discusses current barriers to clinical translation.

Cite this article: E. Ferreira, R. M. Porter. Harnessing extracellular vesicles to direct endochondral repair of large bone defects. Bone Joint Res 2018;7:263–273. DOI: 10.1302/2046-3758.74.BJR-2018-0006.

Objectives

In this study, we compared the pain behaviour and osteoarthritis (OA) progression between anterior cruciate ligament transection (ACLT) and osteochondral injury in surgically-induced OA rat models.

1. Loss of osteocytes in the bone trabeculae of the femoral heads of "normal" elderly patients was patchy and distinguishable from that resulting from avascular necrosis after fracture. 2. Changes in the haemopoietic marrow were the earliest and most sensitive indicators of ischaemia, loss of osteocytes rarely being complete until three or four weeks after fracture. 3. In 109 femoral heads removed more than sixteen days after fracture the viability could be determined by histological means. All of these had suffered some damage to the vascular supply but in a number the head remained alive apart from the region of the fracture line. These heads were nourished by the blood vessels of the ligamentum teres and sometimes by retinacular arteries, usually of the inferior group. 4. Some femoral heads became completely necrotic following fracture, others were only partly affected. A variable amount of the subfoveal region commonly remained alive and it was from this site that revascularisation spread into the head. The upper segment of the femoral head least often remained alive and its subchondral region was usually the last to revascularise. 5. In a group of unselected femoral heads a third remained alive following fracture and two-thirds were partly or completely necrotic. 6. Femoral heads which were partly necrotic appeared capable of uniting and completely revascularising, there being invasion of the necrotic bone by vessels from across the fracture line and from the ligamentum teres. This contrasted with the completely necrotic femoral heads described elsewhere in this issue which united but in the absence of proliferation of ligamenturn teres vessels failed to revascularise completely and developed late segmental collapse. 7. Avascular necrosis did not appear to be the sole cause of non-union. 8. Necrotic bone showed no alteration in radiological density. Reossifying bone in areas of revascularisation sometimes caused an absolute increase of radiodensity especially when associated with halted revascularisation. This increase of radiological opacity was the result of deposition of new on dead bone with broadening of the trabeculae. Marrow calcification was minimal. 9. Obliterative sclerosis of venules in the ligamentum teres was found in "normal" patients even in infancy. No thrombosis was seen in the ligaments following fracture but where the femoral heads were completely necrotic and not revascularised the ligaments were often also necrotic. 10. There appeared to be no increase in degenerative changes in the articular cartilage of the femoral heads following fracture compared with fifty elderly controls. Some loss of chondrocytes in the deep zone of the weight-bearing area was found in about a quarter of the femoral heads. In only one head was the cartilage almost completely acellular. An almost normal depth and a smooth contour of the articular cartilage were retained

1. Autografts, isografts and homografts of fibrocartilaginous callus were observed in the anterior chamber of the eye in rats. Proliferation of cartilage ceased, endochondral ossification followed, and the end-product was a new and complete ossicle with a cortex and a marrow cavity. The size and shape of the ossicle was determined by the size and shape of the sample of callus. Thus the callus in the eye performed the function of a cartilage model like that of the developing epiphysis or a healing fracture of a long bone. 2. Fibrocartilaginous callus, heavily labelled with . 3. H-thymidine, was transplanted to the eye twenty-four hours after the last injection, when there was little if any radioactive thymidine circulating in the blood. A few small chondrocytes with labelled nuclei persisted in the cores of new bone trabeculae, but the largest part of the labelled callus was resorbed and replaced by unlabelled new bone. 3. Homografts of labelled callus produced the same results as autografts at twenty-five days, but between twenty-five and forty-five days the donor cells were destroyed by the immune response of the host. 4. Isogenous transplants in host rats treated with . 3. H-thymidine between nine and thirteen days, when the callus was invaded by new blood vessels, produced many osteogenetic cells with labelled nuclei and made it possible to trace the origin of the new bone. The label appeared in the progenitor cells within twenty-four hours. While remaining thereafter in progenitor cells, it appeared also in osteoclasts (or chondroclasts) and osteoblasts in forty-eight to seventy-two hours, and in osteocytes in ninety-six to 120 hours. Chondrocytes did not proliferate and were not labelled in the eye. 5. Homogenous transplants in host rats treated with . 3. H-thymidine between five and one days before the operation also produced new bone, but contained no labelled osteoprogenitor or bone cells after twenty-five days in the eye. At forty-five days the donor tissue had been destroyed by the immune response of the host. 6. Devitalised callus was encapsulated in inflammatory connective tissue and scar. When the dead callus was absorbed by the capillaries of the host new bone formation by induction produced a scanty deposit as a delayed event in a few instances. 7. Irrespective of whether it originated in the donor or the host, a connective-tissue cell type that proliferated rapidly and became labelled with . 3. H-thymidine was identified as a progenitor cell. Differentiation and specialisation as osteoprogenitor cells occurred after the growth of blood vessels into the interior of the callus, and developed inside of excavation chambers in cartilage. Except that the interaction of the donor tissue and host cells leading to new bone formation by induction takes place in the interior of the excavation chamber, the biophysico-chemical mechanism is unknown