Cut-out risk factor analysis after intramedullary nailing for the treatment of extracapsular fractures of the proximal femur: a retrospective study.

BACKGROUNDS: The basic method of surgical treatment for extracapsular hip fractures (ECFs), including intertrochanteric fracture and basicervical fracture (BCF), is osteosynthesis. Intramedullary nails are among the most commonly used fixation devices for these fractures. Our study aimed to report the clinical outcomes of ECF treatment with two different nail devices and to analyze the risk factors associated with screw cut-out. METHODS: We retrospectively reviewed the medical records of 273 patients (300 cases) from a single institution who underwent surgical treatment for ECF between January 2013 and October 2018. Overall, 138 patients were eligible for the study and were divided into two groups according to the osteosynthesis device used. We evaluated the clinical outcomes of fracture surgery and performed univariate and multivariate regression analyses to identify risk factors associated with screw cut-out in each group. RESULTS: We used proximal femoral nails (group 1) to treat 83 patients and cephalomedullary nails (group 2) to treat 55 patients. Nine cut-outs (group 1, 6 cases; group 2, 3 cases) occurred during follow-up. The patients' high body mass index (BMI) (p = 0.019), BCFs (p = 0.007), non-extramedullary reduction in the anteroposterior and lateral planes (p = 0.032 and p = 0.043, respectively), and anti-rotation screw pull-outs (p = 0.041) showed a positive correlation to screw cut-out in the univariate analysis of group 1. In group 2, only BCFs was positively correlated (p = 0.020). In the multivariate analysis of group 1, the patients' BMIs (p = 0.024) and BCFs (p = 0.024) showed a positive correlation with cut-out. Meanwhile, the multivariate analysis of group 2 did not identify any factors associated with cut-out. CONCLUSIONS: The cut-out risk was significantly higher in the BCF cases, regardless of the nail design used. Considerable attention should be paid to treating such unstable fractures. We expect that new-generation nails using a helical blade, or interlocking derotation and interlocking screws may improve surgical outcomes.

Angiopoietin-2 Enhances Osteogenic Differentiation of Bone Marrow Stem Cells.

Our previous studies revealed that co-transplantation of bone marrow stem cells (BMSCs) and adipose-derived stem cells (ADSCs) can enhance bone regeneration and angiogenesis. However, it is unclear which genes are involved in the regulation of osteogenesis and/or angiogenesis during the co-culturing of BMSCs and ADSCs. The expression patterns of genes associated with osteogenesis and/or angiogenesis were analyzed in osteogenesis-induced BMSCs and ADSCs using an oligonucleotide microarray. Significant difference in the expression patterns of several genes were identified from hierarchical clustering and analyzed on co-cultured BMSCs and ADSCs. Angiopoietin-2 (ANGPT2) and activin receptor-like kinase-1 were significantly down-regulated in co-culture than culture of either BMSCs or ADSCs, while fibroblast growth factor-9 was significantly up-regulated in co-culture. The effect of ANGPT2 in osteogenesis-induced BMSCs was validated using recombinant protein and siRNA of ANGPT2. Treatment of the ANGPT2 protein significantly increased the expressions of osteogenic makers and the intensity of Alizarin red-S staining in BMSCs. Down-regulation of ANGPT2 significantly decreased the expression of osteogenic makers. The treatment of ANGPT2 protein to BMSCs induced significantly increased tube formation in Transwell-co-cultured human umbilical vein endothelial cells (HUVECs) compared with untreated control. ANGPT2 siRNA transfection showed the opposite effects. These results suggest that the treatment of ANGPT2 in BMSCs increase osteogenesis and angiogenesis in vitro, and that the enhancement of osteogenesis and angiogenesis in the co-cultured BMSCs and ADSCs seems to be mediated by a mechanism that makes the activation of ANGPT2 unnecessary. These observations provide the first evidence for positive regulation of osteogenesis by ANGPT2 in vitro. J. Cell. Biochem. 118: 2896-2908, 2017. © 2017 Wiley Periodicals, Inc.

Autophagy in osteoarthritis.

Osteoarthritis is characterized by continuous degeneration of articular cartilage resulting in disability. The death of chondrocytes and the loss of the extracellular matrix are the central peculiarities in cartilage degeneration during osteoarthritis pathogenesis. Autophagy is an essential cellular homeostasis mechanism whereby cellular organelles and macromolecules are recycled to maintain cellular metabolism. Autophagy is reported to be cytoprotective effects for articular cartilage, and osteoarthritis is associated with decreased autophagy. While autophagy is known to be cytoprotective to chondrocytes, its role may vary with differing stages and models of osteoarthritis. Therefore, more in-depth studies on autophagy are needed to determine its impact on cell survival and death in articular cartilage under various in vitro and in vivo conditions. Application of autophagy on osteoarthritis therapeutics will be possible after a profound understanding is established on the role of autophagy in osteoarthritis pathogenesis.

Concave microwell plate facilitates chondrogenesis from mesenchymal stem cells.

OBJECTIVES: To compare in vitro chondrogenesis from bone marrow-derived mesenchymal stem cells using concave microwell plates with those obtained using culture tubes. RESULTS: Pellets cultured in concave microwell plates had a significantly higher level of GAG per DNA content and greater proteoglycan content than those cultured in tubes at day 7 and 14. Three chondrogenic markers, SOX-9, COL2A1 and aggrecan, showed significantly higher expression in pellets cultured in concave microwell plates than those cultured in tubes at day 7 and 14. At day 21, there was not a significant difference in the expression of these markers. COL10A1, the typical hypertrophy marker, was significantly lower in concave microwell plates during the whole culture period. Runx-2, a marker of hypertrophy and osteogenesis, was significantly lower at day 7 in pellets cultured in concave microwell plates than those cultured in tubes. CONCLUSION: Concave microwell plates provide a convenient and effective tool for the study of in vitro chondrogenesis and may replace the use of propylene culture tube.

Stem cells for reutilization in bone regeneration.

Bone is one of the most transplanted tissues. While most bone defects heal spontaneously, critical size defects caused by major trauma/malignant tumor and osteonecrosis of femoral head in young adults pose a great challenge in treatment. While the golden standard in treating bone defects is autologous bone grafting, available bone for grafting is quite limited in an individual. To solve the dilemma, stem cell therapy has been tried as a new modality of treatment in lesions not amenable to autologous bone grafting. While successful results were reported from individual studies, the stem cell therapy is still not an established treatment modality for bone regeneration and needs further assessment. Our focus herein is to introduce stem cell sources that have been investigated so far and review the current status of stem cell reutilization for bone regeneration as well as suggesting future perspectives.

Ridge regeneration of damaged extraction sockets using rhBMP-2: an experimental study in canine.

OBJECTIVES: This study evaluated the dimensional ridge alteration in a buccal-bone-deficient extraction socket, and ridge regeneration following socket grafting accompanied by recombinant human bone morphogenetic protein 2 (rhBMP-2) or a collagen membrane covering. MATERIAL AND METHODS: In five beagle dogs, entire buccal bone of the extracted sockets of premolars was surgically removed and immediately grafted using one of the following graft protocols: (1) sham surgery without any grafting, and grafting with (2) deproteinized bovine bone mineral (DBBM), (3) DBBM/rhBMP-2 and (4) DBBM covered with a collagen membrane (DBBM/Membrane). Quantitative/qualitative analyses were performed radiographically/histologically after 8 weeks. RESULTS: Buccal-deficient extraction sockets healed with significant reduction in buccolingual dimension along the entire length of the socket, but all grafting techniques reduced the dimensional changes compared to the non-grafted control sites. Histologically, sites received DBBM only exhibited minimal regeneration, whereas sites grafted with DBBM/rhBMP-2 or DBBM/Membrane exhibited greater new bone formation extending the entire augmented area. CONCLUSIONS: Buccal-bone-deficiency may lead to significant volume reduction after tooth extraction along the entire length of the socket, and socket grafting accompanied by rhBMP-2 or covered with a membrane can be candidate therapies for preservation of the buccolingual dimension and successful ridge regeneration.

The relationship between osteoarthritis and osteoporosis.

The relationship between osteoarthritis (OA) and osteoporosis (OP), the two most common skeletal disorders related to aging, is controversial. Previous studies suggest that OA is inversely related to OP when studied cross-sectionally and systematically. However, there are differences in the results depending on the parameter used to define OA. The purpose of this review is to analyze and summarize the literature, and derive possible answers to three key questions along with a brief introduction on underlying mechanisms: (1) Is OA correlated to a high bone mineral density (BMD)? (2) Does OA influence the progression of OP or osteoporotic fractures? (3) Does high BMD affect the incidence and progression of OA? A review of the literature suggests that OA is inversely related to OP in general when studied cross-sectionally and systematically. However, when analyzed in individual bones, the BMD of the appendicular skeleton in OA-affected joints may decrease, particularly in the upper extremities. On whether OA influences bone loss or osteoporotic fractures, differences are observed according to the affected joints. The risk for osteoporotic fracture does not seem to decrease despite a high BMD in patients with OA, probably due to postural instability and muscle strength. Low BMD at the lumbar spine is associated with a lower incidence of knee OA although it does not arrest the progression of knee OA.

Apatite-coated collagen sponge for the delivery of bone morphogenetic protein-2 in rabbit posterolateral lumbar fusion.

Bone morphogenetic proteins (BMPs) need an effective delivery system for efficient bone regeneration. In this study, we evaluated the efficiency of an apatite-coated collagen sponge for the long-term delivery of BMP-2 in a rabbit model of lumbar posterolateral fusion. A total of 15 rabbits, divided into three groups, underwent posterolateral lumbar fusion. The first group (control group) received uncoated collagen sponges without BMP-2. The second group (uncoated group) received uncoated collagen sponges with BMP-2 (40 µg each side). The third group (apatite-coated group) received apatite-coated collagen sponges with the same level of BMPs (40 µg each side). All rabbits were euthanized 6 weeks after operation, and the fusion status was assessed by radiographic study, micro-CT, manual palpation, biomechanical study, and histological examination. Fusion rates as determined by radiographic study, micro-CT, and manual palpation showed that the apatite-coated group had a significantly higher rate of fusion than the control group (P = 0.024), while the uncoated group did not (P = 0.083). Biomechanical study showed significantly higher tensile strength in the apatite-coated group than the uncoated group (P = 0.032). Denser trabeculations were found in the apatite-coated group compared with the uncoated group. It is concluded that the use of apatite-coated collagen sponges for BMP-2 delivery enhanced bone regeneration.

In vivo tracking of mesechymal stem cells using fluorescent nanoparticles in an osteochondral repair model.

We devised and tested an in vivo system to monitor the migration of mesenchymal stem cells (MSCs) within the marrow cavity. In vitro studies confirmed that platelet-derived growth factor (PDGF)-AA had the most potent chemotactic effect of the tested factors, and possessed the greatest number of receptors in MSCs. MSCs were labeled with fluorescent nanoparticles and injected into the marrow cavity of nude rats through osteochondral defects created in the distal femur. The defects were sealed with HCF (heparin-conjugated fibrin) or PDGF-AA-loaded HCF. In the HCF-only group, the nanoparticle-labeled MSCs dispersed outside the marrow cavity within 3 days after injection. In the PDGF-AA-loaded HCF group, the labeled cells moved time-dependently for 14 days toward the osteochondral defect. HCF-PDGF in low dose (LD; 8.5 ng/µl) was more effective than HCF-PDGF in high dose (HD; 17 ng/µl) in recruiting the MSCs to the osteochondral defect. After 21 days, the defects treated with PDGF and transforming growth factor (TGF)-ß1-loaded HCF showed excellent cartilage repair compared with other groups. Further studies confirmed that this in vivo osteochondral MSCs tracking system (IOMTS) worked for other chemoattractants (chemokine (C-C motif) ligand 2 (CCL2) and PDGF-BB). IOMTS can provide a useful tool to examine the effect of growth factors or chemokines on endogenous cartilage repair.

Controlled delivery of low-dose bone morphogenetic protein-2 using heparin-conjugated fibrin in the posterolateral lumbar fusion of rabbits.

The heparin-conjugated fibrin (HCF) system has been developed to deliver bone morphogenetic proteins (BMPs) for a long-term period and thus enhance bone regeneration. In the present study, we tested the effectiveness of the delivery system for spinal fusion with a very low dose of BMP-2. A total of 15 rabbits underwent posterolateral lumbar spine, divided into three groups. The control group received only collagen sponges without BMP-2, another group (BMP-only group) received collagen sponges loaded with BMP-2 (10 µg each side), and the last group (BMP/HCF group) received collagen sponges filled with HCF loaded with BMP-2 (10 µg each side). All animals were euthanized 8 weeks after surgery, and the fusion was assessed by radiographs, manual palpation, computed tomography scan, and mechanical testing. No case in the BMP/HCF group or in the control group achieved solid fusion, while all cases in BMP-only group showed evidence of solid fusion. BMP/HCF group had significantly lower fusion rate and tensile strength than BMP-only group at the dose of 10 µg of BMP-2. The HCF long-term delivery system with the low dose of BMP-2 (10 µg) is ineffective for the induction of lumbar posterolateral fusion in the rabbits.

Regenerative medicine for osteonecrosis of the femoral head : present and future.

Cite this article: Bone Joint Res 2023;12(1):5-8.

Regenerative medicine for early osteoarthritis.

The concept of early osteoarthritis (OA) is based on the expectation that if found and treated in the early stage, the progression of the disease might be arrested before affected joints are irreversibly destroyed. This notion of early OA detection can also bear meaning for regenerative medicine (RM) which is purposed to cure a disease by regenerating the damaged tissue. RM can be a category of disease-modifying osteoarthritis drugs (DMOADs) and provide an attractive treatment for OA, restoring structural damage incurred during the disease by repopulating cells and reconstituting. While cell therapy including the use of stem cells is conflated with RM, it may also comprise gene therapy, exosomes, and other cell or cell-free-derived products. Considering that not all early OA will become advanced OA and that RM has a characteristic of personalized medicine, it would be very important to foretell, even roughly, which patients will progress rapidly and who will favorably respond to regenerative treatment. Subclassification and comprehensive endotyping or phenotyping (E/P) can be very helpful in detecting the population who would benefit from RM as well as rapid progressors who need closer monitoring.

GSTT1 as a Predictive Marker and Enhancer for Osteogenic Potential of Human Adipose-Derived Stromal/Stem Cells.

Adipose-derived stromal/stem cells (ASCs) have been extensively studied as cell sources for regenerative medicine for bone because of their excellent proliferative capacity and the ability to obtain a large number of cells with minimal donor morbidity. On the other hand, the differentiation potential of ASCs is generally lower than that of bone marrow-derived stromal/stem cells and varies greatly depending on donors. In this study, we mined a marker that can predict the osteogenic potential of ASC clones and also investigated the usefulness of the molecule as the enhancer of osteogenic differentiation of ASCs as well as its mechanism of action. Through RNA-seq gene analysis, we discovered that GSTT1 (Glutathione S-transferase theta-1) was the most distinguished gene marker between highly osteogenic and poorly osteogenic ASC clones. Knockdown of GSTT1 in high osteogenic ASCs by siGSTT1 treatment reduced mineralized matrix formation. On the other hand, GSTT1 overexpression by GSTT1 transfection or GSTT1 recombinant protein treatment enhanced osteogenic differentiation of low osteogenic ASCs. Metabolomic analysis confirmed significant changes of metabolites related to bone differentiation in ASCs transfected with GSTT1. A high total antioxidant capacity, low levels of cellular reactive oxygen species, and increased GSH/GSSG ratios were also detected in GSTT1-transfected ASCs. When the in vivo effect of GSTT1-transfected ASCs on bone regeneration was investigated with segmental long-bone defect model in rats, bone regeneration was significantly better after implantation of GSTT1-transfected ASCs compared with that of control vector-transfected ASCs. In conclusion, GSTT1 can be a useful marker to screen the highly osteogenic ASC clones and also a therapeutic factor to enhance the osteogenic differentiation of poorly osteogenic ASC clones. © 2023 American Society for Bone and Mineral Research (ASBMR).

PTHrP isoforms have differing effect on chondrogenic differentiation and hypertrophy of mesenchymal stem cells.

While several isoforms of parathyroid hormone-related peptide (PTHrP) have been commercially available, the difference in their effect has not been widely studied. The purpose of this study was to determine which isoform most effectively promoted chondrogenesis and suppressed hypertrophy from mesenchymal stem cells (MSCs). MSCs isolated from fresh bone marrow were cultured in pellet in chondrogenic medium containing 5 ng/ml of transforming growth factor (TGF)-ß(3). From day 14 of culture, subsets of pellets were additionally treated with one of the four PTHrP isoforms (1-34, 1-86, 7-34, and 107-139) at 100 nM. After a further 2 weeks of in vitro culture, pellets were harvested for analysis. PTHrPs 1-34 and 1-86 significantly decreased the DNA level (p<0.05) while PTHrPs 7-34 and 107-139 significantly increased DNA level (p<0.05) compared with the control treated with TGF-ß(3) only. Glycosaminoglycan per DNA significantly increased when treated with PTHrPs 1-34 and 1-86 (p<0.05) while it significantly decreased with PTHrPs 7-34 and 107-139 (p<0.05). PTHrP 1-34 significantly increased the gene and protein expression of the chondrogenic marker COL2A1, and decreased those of hypertrophic markers COL10A1 and alkaline phosphatase while other isoforms showed inconsistent effects. All of PTHrP isoforms significantly suppressed the gene and protein expression of indian hedgehog (p<0.05) while all isoforms except PTHrP 107-139 significantly reduced the gene and protein expression of patched 1 (p<0.05). In conclusion, of several PTHrP isoforms, PTHrP 1-34 most significantly enhanced chondrogenesis and suppressed hypertrophy in MSCs, supporting its use for cartilage tissue engineering.

The relationship between radiological parameters from plain hip radiographs and bone mineral density in a Korean population.

The purpose of this study was to investigate the association of the Singh index, cortical thickness index (CTI) and calcar-to-canal (CC) ratio with bone mineral density (BMD) as well as their relationship with physical parameters [age, gender, height, and body mass index (BMI)] in order to assess their potential as an indirect indicator of osteoporosis. BMD, Singh index, CTI and CC ratio as well as the physical parameters were obtained from hip radiographs and clinical records of 140 Korean adults. Linear relationships between the areal BMD of the femoral neck and the parameters as well as between each parameter were obtained. To determine the association between BMD and the radiological parameters, multiple regression analyses were performed after adjusting for the four physical parameters. The CTI was positively associated with BMD (p = 0.040), whereas the Singh index (p = 0.209) and CC ratio (p = 0.655) were not. The CTI was negatively associated with age (p = 0.02) and positively associated with height (p = 0.0001) and BMI (p = 0.001). The CC ratio was also positively associated with age (p = 0.0001) and negatively associated with height (p = 0.033). In conclusion, of three parameters available from plain radiograph (age, height, BMI), only CTI was significantly associated with BMD. CTI can provide a tool for rapid assessment of osteoporosis from plain hip radiographs.

The clinical effect of locally delivered minocycline in association with flap surgery for the treatment of chronic severe periodontitis: a split-mouth design.

OBJECTIVE: The purpose of this study was to determine the effectiveness of adjunctive application of locally delivered minocycline ointment associated with flap surgery for the treatment of patients with chronic severe periodontitis. MATERIAL AND METHODS: Twenty patients with chronic severe periodontitis were treated in a split-mouth study to either adjunctive application of locally delivered minocycline ointment in association with flap surgery (FM) or flap surgery only (FO); additional minocycline application was performed at 3 months post operation. Clinical evaluation of the plaque index, probing depth (PD), bleeding on probing (BOP), gingival recession, and clinical attachment level (CAL) was conducted at baseline and at 3 and 6 months after treatment. RESULTS: Clinical evaluations revealed that although both sites exhibited clinical improvement, there was a statistically significant reduction in PD (3.34 ± 0.03 mm) and BOP (78.01 ± 11.42%), and a significant gain of CAL (1.88 ± 0.21 mm) at the FM site compared with the FO site (reduction of PD and BOP: 2.62 ± 0.06 mm, 50.33 ± 15.01%, and gain of CAL: 1.55 ± 0.13 mm) at 6 months post operation (p < 0.05). CONCLUSION: Adjunctive application of locally delivered minocycline may be beneficial to the surgical treatment protocol of chronic severe periodontitis.

Acquisition of human alveolar bone-derived stromal cells using minimally irrigated implant osteotomy: in vitro and in vivo evaluations.

OBJECTIVES: Implant osteotomy yields a substantial amount of bone in the form of bone chips entrapped within drill flutes, and can provide a promising cell source for tissue engineering. The aims of this study were to isolate human alveolar bone-derived stromal cells (hABCs) obtained during implant osteotomy, and to evaluate osteogenic differentiation capacity of hABCs. MATERIAL AND METHODS: Bone chips were obtained by minimally irrigated implant drilling technique from 10 human donors. Isolated cells were studied with respect to their colony-forming efficiency, surface marker expression by immunofluorescence staining, fluorescence-activated cell sorting analysis and self-renewal potency. To verify the differentiation activity, in vitro osteogenic and adipogenic gene expressions were evaluated by reverse transcription-polymerase chain reaction, and in vitro formation of mineralized nodule and adipocytes was also evaluated. In vivo bone-forming activity was assessed by ectopic transplantation in immunocompromised mice (n = 5). RESULTS: Human alveolar bone-derived stromal cells population with characteristics of mesenchymal stem cells was present in the isolated cells. Upon hABC transplantation, significant ectopic bone formation was induced with the characteristics of fully matured bone tissue. CONCLUSION: The data support the feasibility of using hABCs as a source of stem cells for dentoalveolar bone tissue reconstruction. The cell source has an advantage that the hABCs can be easily acquired during implant surgery.

Lumbar posterolateral fusion using heparin-conjugated fibrin for sustained delivery of bone morphogenic protein-2 in a rabbit model.

We had devised a heparin-conjugated fibrin (HCF) system to deliver bone morphogenic proteins (BMPs) for a long-term period to enhance bone regeneration. In the present study, we tested the effectiveness of the delivery system for spinal fusion in a rabbit model. A total of 15 rabbits underwent posterolateral lumbar spine fusion with BMP-2 (50 µg per collagen sponge). The control group received only collagen sponges without BMP-2, another group (short-term delivery [SD] group) received collagen sponges filled with fibrin gel loaded with BMP-2, and the third group (long-term delivery [LD] group) received collagen sponges filled with HCF loaded with BMP-2. All animals were euthanized 8 weeks after surgery, and the fusion was assessed by radiographs, manual palpation, computed tomography, and mechanical testing. The fusion rate was significantly higher in the LD group using HCF than in the SD group or in the control group. Biomechanical testing showed the tensile strength was also significantly higher in the LD group using HCF than in other groups. The HCF system can provide a good option for the delivery of BMP-2 on posterolateral lumbar spine fusion.

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.

Emerging Concepts of Endotypes/Phenotypes in Regenerative Medicine for Osteoarthritis.

Osteoarthritis (OA) represents a broad spectrum of different conditions. Our present understanding of phenotypes and endotypes can explain the differences in clinical manifestations, etiology, and underlying pathophysiology. Although this concept was first applied in choosing the right target population for clinical trials of disease-modifying osteoarthritis drugs (DMOADs), given that the regenerative medicine so far has not delivered uniformly successful results in structural improvement in OA, it merits a consideration to introduce the concept of phenotype/endotype in the regenerative medicine for OA toward an effort to find the right patients for these expensive therapeutics. A better understanding of molecular endotypes facilitates defining clinical phenotypes more clearly. Based on this knowledge, these patients may respond better to treatments that can preserve joints, including regenerative medicine. On the other hand, patients who are not expected to benefit from these treatments may receive earlier total joint replacement surgery. This will result in a reduction of healthcare costs, as well as a more effective approach to new drug development. An understanding of phenotypes/endotypes will contribute to the selection of suitable patients for regenerative treatment of OA.