The Concept of Early Osteoarthritis and Its Significance in Regenerative Medicine

Osteoarthritis (OA) has been investigated as one of important target diseases for regenerative medicine. The concept of early OA has recently emerged under the assumption that if OA is detected and intervened early, progression of OA might be arrested or delayed before irreversible destruction of the joint occurs. This concept also matters in regenerative medicine for OA because new regenerative technologies can work better when joint damage is minimal. Diagnostic criteria for early OA have been suggested in this background to find a group of patients who have a higher possibility of developing full-blown OA. However, as currently suggested criteria of early OA are mostly expert opinions lacking higher level of evidence, clinical validations are necessary to prove their value in patient care. While new treatment methods that can suppress or prevent symptoms at an early stage of OA before progressive and irreversible changes occur are being developed, detailed definition and classification of early OA agreed upon by major stakeholders in OA field and validated by prospective studies are necessary to prove the efficacy of these methods. As clinical outcome of regenerative treatment is related to patient characteristics and the status of the whole joint, it is of critical significance to predict which patient will progress and who will be responsive to regenerative treatment. While diagnostic criteria for early OA should be highly sensitive and applicable without employing biomarkers or magnetic resonance imaging, a subclassification and comprehensive endotyping /phenotyping using these techniques might be needed to detect the population who would be responsive to regenerative medicine.

Overcoming Current Dilemma in Cartilage Regeneration: Will Direct Conversion Provide a Breakthrough?

Direct reprogramming/direct conversion/transdifferentiation is a process that induces conversion between completely different matured (differentiated) cells in higher organisms. Unlike the process of reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) and re-differentiation into the desired cell types, differentiated cells undergo the conversion into another type of differentiated cells without going through the iPSCs state. Osteoarthritis (OA) is the most common type of arthritis that causes a significant deterioration in patients’ quality of life. The high prevalence of OA as well as the current lack of disease-modifying drugs has led to a rise in regenerative strategy for OA treatment. Regenerative therapy in OA started with the concept of engraftment of the administered cells within the cartilage lesion and differentiation to chondrocytes after the engraftment. However, recent studies show that cells, particularly when injected in suspension, rapidly undergo apoptosis after exerting a transient paracrine effect. In this perspective review, the general overview and current status of direct conversion are introduced along with the conceptual strategy and future directions for possible application of regenerative therapy using stem cells in OA. In vivo direct conversion may open a new stage of regenerative medicine for OA treatment. Recent advances in in vivo gene transfer and smart biomaterials can bring the concept into reality in near future. Direct conversion can be a new type of treatment technology that has the potential to overcome the limitations of current cell therapy.

Overcoming Current Dilemma in Cartilage Regeneration: Will Direct Conversion Provide a Breakthrough?

Direct reprogramming/direct conversion/transdifferentiation is a process that induces conversion between completely different matured (differentiated) cells in higher organisms. Unlike the process of reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) and re-differentiation into the desired cell types, differentiated cells undergo the conversion into another type of differentiated cells without going through the iPSCs state. Osteoarthritis (OA) is the most common type of arthritis that causes a significant deterioration in patients’ quality of life. The high prevalence of OA as well as the current lack of disease-modifying drugs has led to a rise in regenerative strategy for OA treatment. Regenerative therapy in OA started with the concept of engraftment of the administered cells within the cartilage lesion and differentiation to chondrocytes after the engraftment. However, recent studies show that cells, particularly when injected in suspension, rapidly undergo apoptosis after exerting a transient paracrine effect. In this perspective review, the general overview and current status of direct conversion are introduced along with the conceptual strategy and future directions for possible application of regenerative therapy using stem cells in OA. In vivo direct conversion may open a new stage of regenerative medicine for OA treatment. Recent advances in in vivo gene transfer and smart biomaterials can bring the concept into reality in near future. Direct conversion can be a new type of treatment technology that has the potential to overcome the limitations of current cell therapy.

Stem Cells for the Regeneration of Tendon and Ligament: A Perspective

Tendons are structures that connect muscles to the bones in our body and transmit the force generated by contraction of the muscles to the bones. Ligaments are structures that connect bones to bones, with histological properties similar to tendons. In tendon and ligament tissue, there are very small amounts of cells similar to mesenchymal stem cells (MSCs) called tendon stem/progenitor cells (TSPCs), or tenogenic stem cells. While the role of specific growth factors and transcription factors is well established in the osteogenic and chondrogenic differentiation of stem cells, a consensus has not been established for tenogenic differentiation. Injuries to tendons and ligaments are very common, but natural healing is very slow and inefficient due to limited vascularization. Currently, there is no adequate method for restoring extensive tendon or ligament defects. Procedures addressing the unmet need for regeneration of these tissues are needed. In this review, the current knowledge, as well as the authors’ ideas and perspective on stem cell and regenerative medicine for tendon and ligament defects are presented.

Regenerative Therapy for Osteoarthritis: A Perspective

Osteoarthritis (OA) is the most common type of arthritis and causes a significant deterioration in patients’ quality of life. The high prevalence of OA as well as the current lack of disease-modifying drugs led to a rise in regenerative medicine efforts. The hope is that this will provide a treatment modality with the ability to alter the course of OA via structural modifications of damaged articular cartilage (AC). Regenerative therapy in OA starts with the concept that administered cells may engraft to a lesion site and differentiate into chondrocytes. However, recent studies show that cells, particularly when injected in suspension, rapidly undergo apoptosis after exerting a transient paracrine effect. If the injected stem cells do not lead to structural improvements of a diseased joint, the high cost of cell therapy for OA cannot be justified, particularly when compared with other injection therapeutics such as corticosteroids and hyaluronic acid. Long-term survival of implanted cells that offer prolonged paracrine effects or possible engraftment is essential for a successful cell therapy that will offer durable structural improvements. In this perspective review, the history and current status of regenerative therapy in OA are summarized along with the conceptual strategy and future directionsfor a successful regenerative therapy that can provide structural modifications in OA.

Updates in Cartilage Tissue Regeneration

No abstract available.

Perspective on Intra-articular Injection Cell Therapy for Osteoarthritis Treatment

BACKGROUND: Osteoarthritis (OA), the most common arthritis, is one of the most frequently encountered orthopaedic conditions. As a small number of large joints such as knee and hip are affected in OA, OA is an ideal target for local therapy. Although corticosteroid and hyaluronic acid have been traditionally used for joints through intra-articular (IA) injection, IA injection also provides a minimally invasive route to apply cell therapy to treat OA. IA cell therapy has drawn attention because it may provide regeneration of articular cartilage in addition to palliative anti-inflammatory effects. METHODS: Current progress of IA injection therapy and the author's perspective on this issue are described narratively. RESULTS: It is too premature to have any conclusion on the eventual efficacy of IA cell therapy concerning regeneration of articular cartilage based on current data. Prospective radiological and histological data from larger numbers of patients are needed to prove cost effectiveness of IA cell therapy. CONCLUSION: Expanding research in this field will produce further evidences to provide guidance on the eventual effectiveness of IA cell therapy in the future.

Stem Cell Therapy in Osteonecrosis of the Femoral Head / 대한고관절학회지

No abstract available.

Intra-articular Xenotransplantation of Adipose-Derived Stromal Cells to Treat Osteoarthritis in a Goat Model

Adipose-derived stromal cells (ASCs) have been investigated as a cell source for tissue regeneration. The purpose of this study was first to confirm if medial meniscectomy induces osteoarthritis (OA) in goats within a relative short period of time, and more importantly, to investigate if systemic treatment with immunosuppressive drugs is necessary in intra-articular ASC xenotransplantation for successful regeneration of articular cartilage and prevention of joint inflammation. Eight Korean native black goats 1–2 years of age underwent medial meniscectomy. To evaluate the gross and histological appearance of articular cartilage, knee joints were re-exposed by a medial parapatellar incision at 8 weeks. After macroscopic scoring of gross appearance, cartilage biopsy specimens 6 mm in diameter were obtained from the femoral condyle in four goats. The goats were injected with single intra-articular dose of 7×10₆ human ASCs (hASCs) 7 days after the second arthrotomy. Four animals were treated with daily injections of cyclosporin A 10 mg/kg for 7 days, followed by a reduced dose of 5 mg/kg for another 7 days, while other 4 animals did not receive immunosuppressive therapy. All animals were sacrificed for analysis 8 weeks after injection of hASCs. OA was successfully induced 8 weeks after medial meniscectomy. Eight weeks after injection of hASCs, various signs of articular cartilage regeneration were observed. There were no significant macroscopic and histological differences between goats treated with cyclosporine and untreated goats. Interleukin-1β and tumor necrosis factor-α level from synovial fluid did not differ between cyclosporine-treated and untreated goats. The results indicate that immunosuppressive therapy did not influence the result of ASC xenotransplantation to treat OA.

Effects of Trichostatin A on the Chondrogenesis from Human Mesenchymal Stem Cells

Histone deacetylase inhibitors (HDACi) are a class of compounds that suppress the function of histone deacetylases (HDACs). This study was performed to examine the effects of Trichostatin A (TSA), a typical HDACi, on chondrogenesis of human bone marrow mesenchymal stem cells (hBMMSCs) and related molecular pathways. After evaluating the concentration for cytotoxicity and HDAC activity, hBMMSCs underwent chondrogenic differentiation in pellet culture with or without TSA for 21 days. The weight of TSA-treated pellets was 25% lower than that of untreated pellets. DNA level was not significantly different, but glycosaminoglycan content per DNA level was lower in TSA-treated pellets than that of untreated pellets. Gene expression of the chondrogenic markers (SOX9, Aggrecan, and Col2A1) decreased by by 12.9-fold, 8.9-fold, and 7.6-fold respectively in TSA-treated pellets compared with that in TSA-untreated pellets. TSA-treated pellets had lower cell density and lower proteoglycan staining content compared with those of TSA-untreated pellets. A microarray analysis from TSA-treated pellets showed that 1,467 chondrogenic-related genes were downregulated and 1,524 were upregulated by more than 2-fold compared with TSA-untreated pellets. Col10A1, TGF-β3, and SOX9 decreased significantly by 10-fold, 2.1-fold, and 3.2-fold respectively in TSA-treated pellets compared with those in untreated pellets, whereas expression of BMP4 and FGFR3 increased significantly by 2.1-fold and 5.4-fold respectively. It is concluded that TSAinhibits chondrogenesis and does not seem to be useful for cartilage tissue engineering of hBMMSCs.

Effect of Teriparatide on Healing of Atypical Femoral Fractures: A Systemic Review

BACKGROUND: Bisphosphonates (BPs) are the most commonly used anti-osteoporotic drugs, which have been proven to reduce the risk of osteoporotic fractures. However, use of BPs, particularly for long periods of time, is associated with an increased risk of atypical femoral fracture (AFF). Healing of BP-associated AFF is usually delayed because of suppressed bone turnover. Teriparatide (TPTD), a recombinant form of parathyroid hormone (PTH), enhances bone healing in patients with delayed healing or non-union. METHODS: In this study, we summarized and performed a systemic review of the published literature on treatment of AFF using TPTD. RESULTS: Although there is a lack of level 1 studies on the evidence of TPTD in promoting bone union in AFFs, this systemic review of the available literature revealed that TPTD works positively in AFFs, and we put together the evidence that TPTD is a viable treatment option for enhancing fracture healing in AFFs. CONCLUSIONS: While anecdotal evidence of beneficial effects of TPTD on fracture healing offer limited guidance for clinical decision making, a better understanding of the role of TPTD in fracture healing may be elucidated with future prospective trials.

Pathogenesis, Management and Prevention of Atypical Femoral Fractures

Much attention has been paid to the relationship between atypical femoral fractures (AFF) and use of bisphosphonates (BPs). While a significant cause-effect relationship was not established in earlier studies, more recent data shows a growing relationship between AFF and BPs use. The definition of an 'AFF' has also undergone significant changes. This review briefly summarizes the definition, pathogenesis, and management of AFF.

The Relationship between Osteoarthritis of the Knee and Bone Mineral Density of Proximal Femur: A Cross-Sectional Study from a Korean Population in Women

BACKGROUND: The relationship between osteoarthritis (OA) and osteoporosis (OP) is complicated and it may differ according to the site or stage of disease. The purpose of this cross-sectional study is to examine the relationship between the severity of radiological knee OA and the degree of OP in the ipsilateral proximal femur as denoted by bone mineral density (BMD) in a Korean population, especially among women. METHODS: One hundred ninety-five female patients who had knee pain and radiological knee OA were investigated with respect to the relationship of knee OA severity with BMD. The BMD of the proximal femur and spine was measured by dual energy X-ray absorptiometry, and the severity of knee OA was evaluated based on Kellgren-Lawrence (K-L) radiographic criteria, joint space narrowing (JSN) and mechanical axis of knee alignment. Partial correlation analysis and ANCOVA adjusted for confounding factors (age and body mass index) were performed to assess the relationship. RESULTS: There was a statistically significant relationship between the BMD of the proximal femur and JSN, and the BMD of the proximal femur was positively associated with increased joint space width. There was a lack of association between the spine BMD and JSN. The BMD of the proximal femur was also significantly lower in patients who had a higher K-L grade. CONCLUSIONS: The radiographic finding of severe OA in the knee is associated with decreased BMD of the ipsilateral proximal femur including the femoral neck, trochanter, intertrochanter, and region of the entire hip (neck, trochanter, and Ward's triangle).

Current Status of Basic Research in Orthopaedics / 한양의대학술지

Orthopaedic medicine has developed and benefited from the advancement of related basic science. Current technologies such as joint replacement and internal fixation of fractures started from research on biocompatible biomaterials and on the understanding of body biomechanics. As ongoing research on life science may dramatically change the appearance of future orthopaedic medicine, it is very important to keep abreast with recent trends of related basic science. This review introduces the realm of basic sciences related to orthopaedic medicine along with comments on future perspectives.

Novel analysis model for implant osseointegration using ectopic bone formation via the recombinant human bone morphogenetic protein-2/macroporous biphasic calcium phosphate block system in rats: a proof-of-concept study

PURPOSE: The osseointegration around titanium mini-implants installed in macroporous biphasic calcium phosphate (MBCP) blocks was evaluated after incubation with recombinant human bone morphogenetic protein-2 (rhBMP-2) in an ectopic subcutaneous rat model. METHODS: Mini-implants (phi1.8x12 mm) were installed in MBCP blocks (bMBCPs, 4x5x15 mm) loaded with rhBMP-2 at 0.1 mg/mL, and then implanted for 8 weeks into subcutaneous pockets of male Sprague-Dawley rats (n=10). A histomorphometric analysis was performed, and the bone-to-implant contact (BIC) and bone density were evaluated. RESULTS: Significant osteoinductive activity was induced in the rhBMP-2/bMBCP group. The percentage of BIC was 41.23+/-4.13% (mean+/-standard deviation), while bone density was 33.47+/-5.73%. In contrast, no bone formation was observed in the bMBCP only group. CONCLUSIONS: This model represents a more standardized tool for analyzing osseointegration and bone healing along the implant surface and in bMBCPs that excludes various healing factors derived from selected animals and defect models.

Enhanced skin wound healing by a sustained release of growth factors contained in platelet-rich plasma

Platelet-rich plasma (PRP) contains growth factors that promote tissue regeneration. Previously, we showed that heparin-conjugated fibrin (HCF) exerts the sustained release of growth factors with affinity for heparin. Here, we hypothesize that treatment of skin wound with a mixture of PRP and HCF exerts sustained release of several growth factors contained in PRP and promotes skin wound healing. The release of fibroblast growth factor 2, platelet-derived growth factor-BB, and vascular endothelial growth factor contained in PRP from HCF was sustained for a longer period than those from PRP, calcium-activated PRP (C-PRP), or a mixture of fibrin and PRP (F-PRP). Treatment of full-thickness skin wounds in mice with HCF-PRP resulted in much faster wound closure as well as dermal and epidermal regeneration at day 12 compared to treatment with either C-PRP or F-PRP. Enhanced skin regeneration observed in HCF-PRP group may have been at least partially due to enhanced angiogenesis in the wound beds. Therefore, this method could be useful for skin wound treatment.

The Usefulness of Bone Turnover Marker as a Predictive Factor In Osteopenic Postmenopausal Women / 대한정형외과연구학회지

PURPOSE: To assess the relationship between biochemical bone turnover marker and bone mineral density(BMD) and to evaluate the predictive role of biochemical bone marker in postmenopausal osteopenic woman. MATERIALS AND METHODS: Ninety two postmenopausal women (50-65 years old), who have the T-score from -1.0 to -2.5 by the dual-energy X-ray absorptiometry (DEXA), were examined consecutively with BMD of the lumbar spine and biochemical bone turnover marker including urine Cross-linked N-telopeptide of type I collagen (u-NTX), urine deoxy-pyridinoline (u-DPD), serum Cross-linked C-telopeptide of type I collagen (s-CTX), serum bone-specific alkaline phosphatase (s-BAP), serum osteocalcin (s-OC) for six months. We evaluated the relation between the changes in the biochemical markers and the rate of bone loss. RESULTS: Seventy four postmenopausal women completed this study. All biochemical bone turnover marker and BMD at one time point including the baseline and the end point did not show any significant correlation. Another longitudinal study found no significant correlation between the baseline biochemical bone turnover marker and the change in lumbar spine BMD. The other study showed significant correlation between the changes in s-CTX/s-OC and the change in lumbar spine BMD (p=0.04, 0.03). The changes of u-NTX and s-OC were larger in the group of aggravation in BMD (p=0.032, 0.041). CONCLUSION: The relationship between bone turnover marker and BMD at one time point was not clear. The predictive role of baseline bone turnover marker was limited to predict the magnitude of changes in lumbar BMD in untreated osteopenic individuals. The changes of s-OC showed significant predictive role in the bone loss in osteopenic postmenopausal women.

The Correlations of the Radiological Parameters of Hip Dysplasia and Proximal Femoral Deformity in Clinically Normal Hips of a Korean Population

BACKGROUND: The aim of this study was to answer the following two questions: 1) Do the radiological parameters of dysplasia have significant correlations between themselves or with the parameters of the proximal femoral deformity and vice versa? 2) Do the physical parameters have a significant correlation with the radiological parameters of hip dysplasia and proximal femoral deformity? METHODS: Four hundred and twenty eight consecutive patients with no clinical evidence of hip osteoarthritis and who underwent pelvic radiography in the supine position for hip contusion or a routine health check were analyzed for the relationships between the center-edge (CE) angle, acetabular depth, acetabular angle, the head-neck ratio and the neck-shaft angle as well as the relationships of the above-mentioned variables with age, gender, body height and the body mass index. RESULTS: The CE angle, acetabular depth and acetabular angle showed a strong correlation with each other. The neck-shaft angle and the head-neck ratio showed no correlation with each other or with the CE angle, acetabular depth and acetabular angle. Age was positively associated with the CE angle, and inversely associated with the acetabular depth or acetabular angle. Male gender was significantly associated with the increased neck-shaft angle, and inversely associated with the head-neck ratio. CONCLUSIONS: The radiological parameters of hip dysplasia are all strongly, if not perfectly, inter-correlated. Age was associated with the radiological parameters of hip dysplasia whereas gender was associated with the radiological parameters of a proximal femoral deformity.

Bone Regeneration from Adipose Stem Cells

Reconstruction of large bone defect poses a great challenge to an orthopedic surgeon. Recent advancement in stem cell research ushered the treatment of bone defect with tissue-engineered bone into near-possibility. While adipose stem cells (ASCs) are the most available cell sources for tissue regeneration, their low osteogenic potential is a disadvantage. Several strategies have been developed to enhance the osteogenic differentiation of ASCs. In this review, we summarized literatures and our experience on the technology to promote osteogenesis from ASCs.

Evaluation of the Hip

The hip is a true ball and socket joint. The hip joint is held in place with ligaments, tendons, and muscles. It is surrounded by a series of bursae which are fluid filled sacs designed to cushion the area. Hip pain may arise from the joint itself, the femur, the pelvic bone, the pelvis, blood vessels and nerves near the hip joint, and even the abdomen. It is important to differentiate true hip pain from other types of pain in the hip region. True hip pain is felt towards the front, in the groin region. It may radiate down the front of the thigh. Physical examination can point to the correct diagnosis. The skilled physician will evaluate range of motion as well as those factors which reproduce the pain. The diagnosis of hip disease usually requires the use of radiologic imaging. The imaging studies include plain films, arthrography, computed tomography (CT) scanning, ultrasound, nuclear imaging, and magnetic resonance imaging (MRI).