Micro-computed tomography assessment of osteochondral microstructural properties of the distal femur and proximal tibia was comprehensively conducted to compare adult patients with knee rheumatoid arthritis (RA) and primary knee osteoarthritis (KOA), with special focus on the effects of knee malalignment. This study encompassed 402 bone samples divided into three groups: the RA group [patients who were subjected to total knee arthroplasty (TKA) due to RA, n = 23, age: 61 ± 10 years], the KOA group [individuals subjected to TKA due to KOA, n = 24, age: 71 ± 9 years] and the control group [sex-matched cadavers without degenerative knee diseases, n = 20, age: 67 ± 11 years]. Our data revealed that the RA, KOA, and control groups differ significantly in osteochondral microstructural properties depending on the knee alignment. Specifically, increasing femoral and tibial cortical porosity, coupled with thinner articular cartilage, were noted in the RA and KOA groups, compared to the controls. Furthermore, larger femoral and tibial cortical pores, lower tibial and femoral subchondral trabecular bone fraction, and thinner tibial articular cartilage were noted in the RA group in comparison to the KOA group, implying that the medial-to-lateral load distribution in the knee joint could be most affected in these patients. Our data illustrated that the thinnest cartilage, a thicker and less porous cortex, along with lower trabecular bone volume, were present in the lateral femoral and tibial condyles of RA individuals with valgus knee alignment. Observed subchondral trabecular microarchitectural alterations could be morphological factors contributing to different effects of surgical treatment and variable implant stability in individuals with RA, warranting further research.

Osteoarthritis (OA), a prevalent degenerative joint disease, presents a formidable challenge to human health due to its complex pathophysiology. Despite various clinical treatments, a definitive cure for OA remains elusive, leaving patients with only symptomatic relief. Tissue engineering has emerged as a promising approach for OA treatment, offering the potential to restore damaged cartilage and osteochondral tissues. Collagen-based scaffolds, renowned for their superior biocompatibility and bioactivity, hold significant potential in promoting effective cartilage and osteochondral regeneration. Over the past decades, substantial progress has been made in the design and clinical translation of collagen-based scaffolds for cartilage and osteochondral tissue engineering. However, no comprehensive review has yet addressed the application of collagen scaffold materials for OA treatment. This review highlights the advanced fabrication of collagen-based scaffolds, including porous matrices, hydrogels, and microspheres, and their integration with cells, growth factors, and pharmaceuticals for OA therapy. Additionally, it examines the clinical translation of collagen-integrated constructs for managing OA. With continued innovation, collagen-enriched scaffolds are expected to play a pivotal role in improving outcomes for OA patients.

Sports activities lead to loading stress for the osteochondral unit of the joints, especially for the lower extremity. Athletes frequently suffer from articular cartilage defects, meniscus and ligament injuries, which are often associated with subchondral bone marrow edema and osteonecrosis.

Presentation of relevance, prognosis and therapeutic options for bone marrow edema and osteonecrosis in sport.

This review describes the clinical relevance, prognostic aspects and potential treatment options for bone marrow edema and osteonecrosis in athletes.

Subchondral bone marrow edema and osteonecrosis frequently occur in athletes. Most commonly, they are caused by mechanical joint overload due to sporting activities, but they are also found posttraumatically and postoperatively. Their clinical relevance to athletes remains unclear. A stepwise treatment concept includes non-surgical as well as surgical treatment options for symptomatic bone marrow edema and osteonecrosis in sport with different clinical prognoses depending on severity and location of the lesion.

Bone marrow edema and osteonecrosis may have a relevant impact on the joint function in athletes. They play a decisive role in the rehabilitation following joint injuries and surgeries and are associated with the clinical outcomes following joint injuries and have critical influence on the return to sporting activities.

IV, narrative review.

Subchondral insufficiency fractures of the knee (SIFK) are a relatively common cause of knee pain, particularly in middle-aged and older adults. The SIFK is a type of stress fracture that occurs when excessive and repetitive or supraphysiologic loads are applied to subchondral bone [1]. Historically, this type of fracture was termed spontaneous osteonecrosis of the knee (SONK) until advances in MRI identified underlying fractures as well as meniscal deficiency as likely attributable etiologies. Consequently, SIFK has replaced SONK as the more appropriate term to refer to this category of conditions, with SONK now viewed as an advanced SIFK lesion. With greater availability of MRI, SIFK has been more frequently recognized and not as commonly mistaken for knee osteoarthritis as it had been in the past, with important implications for treatment and management of this condition.

The endplate region of the vertebra, which includes the bony endplate (BEP) and underlying subchondral trabecular bone (STB), is critically involved in vertebral fracture (VF). While evidence abounds that failure initiates in the endplate region, the relative risk of failure of the BEP vs. STB has not been established. In this study, micro-finite element models were constructed of L1 vertebrae (n = 21) that were mechanically tested in a prior study and given experimentally matched boundary conditions corresponding to the vertebra's yield point. Volumes of interest (VOIs) were defined corresponding to the BEP and STB; the remainder was defined as the mid-vertebral body (MVB). The proportion of elements within each VOI that yielded was defined as the VOI yield fraction, and this value divided by the yield fraction of the entire model was defined as the normalized yield fraction. While yield fraction did not differ across VOIs (p = 0.179), normalized yield fraction was greater in the BEP than STB and MVB (p < 0.001), indicating a higher risk of yield in the BEP compared to the other two VOIs. None of the yield fractions was correlated with BEP or STB microstructure, and tension (rather than compression) was the dominant mode of tissue level yield. These findings indicate that the BEP, more so than the STB, is likely the site of VF initiation and that current methods of screening for VF risk, because they omit specific analysis of the BEP, are missing the region that matters the most. The endplate region of the vertebra, which includes the bony endplate (BEP) and underlying subchondral bone (SB), is critically involved in vertebral fracture (VF). While evidence abounds that failure initiates in the endplate region, the relative risk of failure of the BEP vs. SB has not been established. In this study, micro-finite element models were constructed of L1 vertebrae (n = 21) that had been mechanically tested in a prior study, and they were given experimentally matched boundary conditions corresponding to the vertebra's yield point. Volumes of interest (VOIs) were defined corresponding to the BEP and SB; the remainder was defined as the mid-vertebral body (MVB). The proportion of yielded elements within each VOI was defined as the VOI yield fraction, and this value divided by the yield fraction of the entire model was defined as the normalized yield fraction. While yield fraction did not differ across VOIs (p = 0.179), normalized yield fraction was greater in the BEP than SB and MVB (p < 0.001), indicating a higher risk of yield in the BEP compared to the other two VOIs. None of the yield fractions was correlated with BEP or SB microstructure, and tension (rather than compression) was the dominant mode of tissue level yield. These findings indicate that the BEP, more so than the SB, is likely the site of VF initiation and that current methods of screening for VF risk, because they omit specific analysis of the BEP, are missing the region that matters the most.

The first metacarpal osteotomy is a joint-preserving surgery for thumb carpometacarpal (CMC) osteoarthritis that improves pain and function. However, its effects on joint remodeling and articular cartilage repair under physiological conditions remain unclear. This study aimed to clarify these aspects using computed tomography (CT)-based subchondral bone density analysis and arthroscopic evaluation.

Fifteen hands of 14 patients who underwent a first metacarpal extension-abduction osteotomy for thumb CMC osteoarthritis were included. CT scans were performed preoperatively and one year postoperatively to assess changes in subchondral bone density (measured in Hounsfield units [HU]) across nine regions of the first metacarpal and trapezium articular surfaces. Arthroscopic evaluation of the articular cartilage was performed at the time of osteotomy and at implant removal one year postoperatively using the International Cartilage Repair Society (ICRS) grading scale.

Preoperatively, higher HU values (median [interquartile range]) were observed in the palmar regions of the first metacarpal (758 [643-803] HU) and the central regions of the trapezium (898 [867-960] HU). One year after osteotomy, these values decreased significantly in these initially high-stress regions (first metacarpal palmar regions: 433 [307-475] HU, p <.001; trapezium central regions: 571 [508-649] HU, p <.001; Wilcoxon matched-pairs signed rank test), indicating a more uniform stress distribution. Arthroscopic evaluation revealed improvements in ICRS grade in five out of nine cases on the metacarpal side and four out of nine cases on the trapezium side.

The first metacarpal extension-abduction osteotomy alters the abnormal stress distribution patterns in thumb CMC osteoarthritis, leading to a more uniform stress distribution across the joint. Arthroscopic findings suggest that articular cartilage repair may occur following osteotomy. These results provide new insights into the mechanisms underlying the clinical benefits of this procedure and support its use as a joint-preserving surgery for thumb CMC osteoarthritis.

Cartilage microfracturation is a surgical technique specifically designed to address chondral defects, which are injuries to the cartilage that covers the ends of bones in joints. These defects can result from traumatic injuries, degenerative conditions such as osteoarthritis, or congenital abnormalities. The primary objective of microfracture surgery is to promote the regeneration of functional cartilage tissue, thereby restoring joint function, alleviating pain, and enhancing mobility. The procedure involves creating small, controlled perforations, or microfractures, in the subchondral bone plate beneath the damaged cartilage. This process, performed with precision to minimize damage to surrounding healthy tissue, penetrates the subchondral bone to reach the bone marrow, which is rich in mesenchymal stem cells (MSCs).

Osteochondral defect regeneration is challenging due to the mismatch between cartilage and subchondral bone. We developed a functionalized scaffold replicating the natural architecture, biochemical and biomechanical environment of both tissues to promote concurrent regeneration. Our bilayered, zone-specific scaffold combines tailored materials for each tissue type: gelatin methacryloyl (GelMA), modified hyaluronic acid, and umbilical cord-derived extracellular matrix (ECM) for the cartilage layer; GelMA, placenta-derived ECM, and nano amorphous calcium phosphate for the osseous layer. Using 3D digital light-processing printing, we constructed the scaffold with spatially distributed biochemical and biomechanical signaling. This approach created dual chondro-/osteogenic microenvironments facilitating bone marrow mesenchymal stem cell differentiation. In vivo studies demonstrated concurrent regeneration of cartilage and subchondral bone tissues with robust integration. This 3D-printed biomimetic scaffold, featuring dual-lineage inductive properties, shows promising potential for efficient osteochondral regeneration and addresses complex tissue engineering requirements.

Osteochondritis dissecans (OCD) and osteochondrosis (OC) are multifactorial developmental joint diseases that can occur in various anatomical locations, including the tarsus of immature, rapidly growing large breed dogs. The pathogenesis of canine OCD and OC involves a disruption in endochondral ossification, resulting in a failure of matrix calcification and vascular invasion. This study aimed to investigate the subchondral bone density changes in Labrador Retrievers with tarsocrural OCD/ OC.

A total of 8 dogs with unilateral tarsocrural OCD/ OC were included in the study and density was evaluated with Computed Tomography osteoabsorptiometry (CTOAM ). The findings revealed a significant decrease in subchondral bone density at the location of the OCD/ OC lesion, particularly at the medial trochlear ridge. This area of low density was surrounded by a higher density rim. Furthermore, the contralateral joint showed a significantly higher overall mineral density.

These results highlight the significant changes in bone mineral density associated with tarsocrural OCD/ OC. The lower density in the affected joint suggests pathological alterations in the subchondral bone, which may impact the bone turnover and contribute to the development of secondary osteoarthrosis, subsequently. The higher density observed in the contralateral joint emphasizes the role of altered joint loading and adaptation in the subchondral bone.

Bone marrow lesions (BMLs) of the knee are a common magnetic resonance imaging finding and are present in a wide range of pathologies, including traumatic contusions and fractures, following cartilage surgery alterations, osteoarthritis, transient BMLs syndromes, subchondral insufficiency fractures of the knee and spontaneous osteonecrosis of the knee. Regardless of their aetiology, clinical management may prove challenging. This review focuses on the conservative treatment approaches to manage patients affected by knee BML, thanks to the contribution of field experts.

Experts from around the globe were involved in performing a review on the most used conservative treatment strategies to address BMLs, trying to summarize the available evidence from the most popular first-line treatments while documenting their applications and results for the different BML aetiologies.

Positive results were documented for unloading knee braces, external shockwave therapy, hyperbaric oxygen therapy, pulsed electromagnetic fields therapy and bisphosphonates. Nonetheless, the analysis of the scientific literature documented a scarce number of publications specifically addressing the knee joint, with even less evidence when it comes to the results for the different aetiologies of BMLs.

The management of BMLs is challenging, and many factors influence clinical and radiological outcomes. This paper summarized the evidence on conservative treatments for knee BMLs. Although showing promising results, conservative options still need to be fully investigated. Open questions to be addressed concern treatment duration, BML stage and overlapping with concomitant therapies. Further studies are needed to identify the best first-line conservative approach or treatment combination based on each BML aetiology.

Level V: expert opinion.

The musculoskeletal system relies on critical tissue interfaces for its function; however, these interfaces are often compromised by injuries and diseases. Restoration of these interfaces is complex by nature which renders traditional treatments inadequate. An emerging solution is three-dimensional printing, which allows for precise fabrication of biomimetic scaffolds to enhance tissue regeneration. This review summarizes the use of 3D printing in creating scaffolds for musculoskeletal interfaces, mainly focusing on advanced techniques such as multi-material printing, bioprinting, and 4D printing. We emphasize the significance of mimicking natural tissue gradients and the selection of appropriate biomaterials to ensure scaffold success. The review outlines state-of-the-art 3D printing technologies, varying from extrusion, inkjet and laser-assisted bioprinting, which are crucial for producing scaffolds with tailored mechanical and biological properties. Applications in cartilage-bone, intervertebral disc, tendon/ligament-bone, and muscle-tendon junction engineering are discussed, highlighting the potential for improved integration and functionality. Furthermore, we address challenges in material development, printing resolution, and the in vivo performance of scaffolds, as well as the prospects for clinical translation. The review concludes by underscoring the transformative potential of 3D printing to advance orthopedic medicine, offering a roadmap for future research at the intersection of biomaterials, drug delivery, and tissue engineering.

This study aimed to quantitatively analyze subchondral vascularization during the progression of osteoarthritis (OA) in the elderly, particularly regarding the timing of initial blood vessel emergence and when their density peaks. A total of 129 independent areas from 43 human femoral heads, obtained through arthroplasty for OA or hemiarthroplasty for fractures, were analyzed. The femoral heads were grouped by Kellgren-Lawrence (KL) grades: KL 1 (6 heads), KL 2 (14 heads), KL 3 (10 heads), and KL 4 (13 heads), and the Mankin score was assessed. Quantitative measurements of blood vessel length 1 mm below the tidemark, cartilage volume and thickness, chondrocyte volume, ECM volume, subchondral bone volume, and bone marrow volume were performed using stereology and immunohistochemistry. The most substantial increase in the characteristics of blood vessels within the subchondral region began at KL 3 and peaked at KL 4. Blood vessel volume increased from 6.71 ± 5.84 mm3 in group KL 1 to 156.21 ± 138.67 mm3 in group KL 4 (p < 0.001). Blood vessel surface area showed an increase from 14.78 ± 9.89 cm2 (group KL 1) to 125.20 ± 93.18 cm2 (group KL 4) (p < 0.001). Likewise, blood vessel length grew from 27.53 m (IQR 13.70-65.41 m) in group KL 1 to 112.03 ± 76.07 m in group KL 4 (p = 0.001). This study offers deeper insights into the role of vascularization in OA pathophysiology, quantifying subchondral blood vessel characteristics in the femoral head across different OA stages.

To determine if subchondral bone damage can influence the clinical results of intraarticular platelet-rich-plasma (PRP) treatment in knee osteoarthritic patients.

A retrospective review of patients treated with intraarticular PRP injections for knee osteoarthritis who previously underwent a magnetic resonance (MR) of the knee was performed. Visual Analogic Score (VAS) was assessed for pain, whereas WORMS MR score was adapted to assess the damage to the subchondral bone (WORMSsc score).

Sixty-one patients were treated with 3 weekly injections of PRP. Mean VAS reduction was 27.67±13.13 points (p<.005). WORMS sc mean score was 32±18.5 points. No correlation between WORMSsc and VAS was found. A moderate correlation between WORMSsc score and preoperative VAS was found (r=.43; p<.005).

There is no correlation between the damage to the subchondral bone assessed by MR and pain relief at 12 weeks in patients treated with intraarticular platelet-rich plasma in patients with knee osteoarthritis. A greater damage to the subchondral bone could be associated with more pain.

To determine if subchondral bone damage can influence the clinical results of intraarticular platelet-rich-plasma (PRP) treatment in knee osteoarthritic patients.

A retrospective review of patients treated with intraarticular PRP injections for knee osteoarthritis who previously underwent a Magnetic Resonance (MR) of the knee was performed. Visual Analogic Score (VAS) was assesed for pain, whereas WORMS MR score was adapted to assess the damage to the subchondral bone (WORMSsc score).

Sixty-one patients were treated with 3 weekly injections of PRP. Mean VAS reduction was 27.67±13.13 points (P<.005). WORMS sc mean score was 32±18.5 points. NO correlation between WORMSsc and VAS was found. A moderate correlation between WORMSsc score and Preoperative VAS was found (r=.43; P<.005).

There is no correlation between the damage to the subchondral bone assesed by MR and pain relief at 12 weeks in patients treated with intraarticular platelet-rich plasma in patients with knee osteoarthritis. A greater damage to the subchondral bone could be associated with more pain.

This study aimed to evaluate the clinical and functional outcomes of autologous bone grafting with spheroid-based matrix-induced autologous chondrocyte implantation (MABCI) for osteochondral defects of the knee by analysing pre- and postoperative patient-reported outcome measures (PROMs). Postoperative gait analysis was conducted and compared with a matched healthy control group to investigate biomechanical deviations.

A total of 35 patients (m: 21, f: 14; mean defect size: 4.2 ± 2.4 cm², localisation: femoral condyle: 31, patellofemoral: 5) were analysed. The mean follow-up was 42.6 ± 22.8 months. International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Outcome Score (KOOS), PROMIS 29 profile, and a questionnaire on patient perception of treatment success were assessed to evaluate PROMs. 3D-instrumented gait analysis (GRAIL, Motek) was used to assess lower extremity kinematics, kinetics and vertical ground reaction forces, compared to sex-, age- and body mass index-matched healthy controls.

All clinical scores showed significant improvement compared to the preoperative condition (IKDC: 73.1 ± 10.1 vs. 56.6 ± 17.2, p < 0.01; KOOS subcategories: pain 82.0 [±12.7] vs. 70.7 [±16.7] [p < 0.01], symptoms 79.1 [±20.3] vs. 68.9 [±13.9] [p < 0.01], activities of daily living 90.1 [±11.2] vs. 80.5 [±15.6] [p < 0.01], sport and recreational function: 65.3 [±19.3] vs. 51.3 [±26.29] [p < 0.01], quality of life 52.2 [±18.6] vs. 42.6 [±18.6] [p < 0.01]; numeric pain rating scale: 2.7 ± 2.0 vs. 5.0 ± 2.5, p < 0.01). The analysed patients reported a high satisfaction rate (94.3%). Self-selected walking speed was significantly lower than in healthy controls (1.17 ± 0.17 m/s vs. 0.98 ± 0.18 m/s, p < 0.01). Peak knee flexion angle (PKA) during loading response was significantly smaller (9.6° ± 7.0 vs. 17.7° ± 4.6, p < 0.01), and knee extension moment was significantly reduced (0.1 Nm/kg ± 0.2 vs. 0.4 Nm/kg ± 0.2, p < 0.01).

MABCI is an effective treatment for osteochondral knee defects, showing significant improvements in all evaluated PROMs. Postoperative gait analysis revealed abnormal gait patterns, including reduced PKA and lower knee extension moment, suggesting a need for further rehabilitation to optimise functional recovery.

Level III.

Subchondral bone cysts (SBCs) can significantly impact the outcomes of cartilage repair procedures such as autologous chondrocyte implantation (ACI). However, the etiology and progression of SBCs following ACI remain poorly understood. This case report highlights a progressively enlarging SBC following ACI using all-suture anchors, treated with autologous osteochondral transplantation (AOT).

A 58-year-old female with progressive right knee pain, varus alignment, and Kellgren-Lawrence grade 3 osteoarthritis underwent atelocollagen-associated ACI combined with medial opening wedge high tibial osteotomy. Longitudinal radiological assessment revealed bone hole enlargement corresponding to all-suture anchor sites, with one hole continuing to expand up to 15 months postoperatively, reaching a size of 11 × 13 × 13 mm. This expanding SBC exhibited a connection to the joint cavity via a tiny fissure, scant osteosclerotic rim on CT, and fluid intensity on MRI. Histological analysis of tissue obtained during subsequent AOT revealed several findings. The SBC was located at the anterior portion of the medial femoral condyle, just beneath the all-suture anchor. Osteochondral necrosis was observed surrounding the anchor site, with no evidence of foreign body reaction. The cyst was filled with a mucoid substance and featured an aggregation of foamy macrophages. A sclerotic wall indicative of a strain response was observed. Notably, the presence of osteoclasts along the adjacent bone surface indicated ongoing bone resorption. The patient underwent AOT, which resulted in confirmed bone union. Postoperative follow-up demonstrated successful integration of the osteochondral graft and improved knee function scores over three years.

This case report documents SBC formation following knee surgery with all-suture anchors and provides histological evaluation of such a cyst. The observed histological findings may contribute to our understanding of SBC pathophysiology in the context of cartilage repair procedures. This case underscores the importance of secure suturing techniques in high-stress areas and suggests the potential benefit of extended post-operative monitoring of SBC progression beyond one year. These observations may inform future strategies for the early detection of SBC formation and its progression, as well as timely intervention to prevent further joint damage in similar cases, though further research is needed to establish broader clinical implications.

Osteoarthritis (OA) represents a condition under the influence of central nervous system (CNS) regulatory mechanisms. This investigation aims to examine the causal association between viral infections of the central nervous system (VICNS) and inflammatory diseases of the central nervous system (IDCNS) and knee osteoarthritis (KOA) at the genetic level.

In this investigation, VICNS and IDCNS were considered as primary exposure variables, while KOA served as the primary outcome. Employing a two-sample mendelian randomization (MR) approach, we conducted an analysis utilizing summary data derived from genome-wide association studies (GWAS). The GWAS summary data pertaining to VICNS and IDCNS were procured from the Finnish consortium, whereas the IEU OpenGWAS database furnished the requisite data for KOA. To ensure the robustness of our genetic causal assessment, a comprehensive array of sensitivity analyses was undertaken, encompassing evaluations of heterogeneity, horizontal pleiotropy, outlier identification, leave-one-out analyses, and assessment of the normal distribution.

The results of the MR analyses revealed a suggestive positive genetic causal relationship between VICNS and KOA (P = 0.012, odds ratio [OR] with a 95% confidence interval [CI] of 1.033 [1.007-1.059]). Conversely, the MR analyses did not indicate any evidence of genetic causation between IDCNS and KOA (P = 0.575, OR 95% CI = 0.986 [0.940-1.035]). Importantly, the genetic causal assessment of the exposure and outcome variables did not demonstrate any indications of heterogeneity, horizontal pleiotropy, or outliers. Furthermore, this assessment remained robust against the influence of individual single nucleotide polymorphisms (SNPs) and exhibited adherence to a normal distribution.

The result of this study has elucidated a suggestive positive genetic causal link between the VICNS and KOA. However, no such genetic causal relationship was observed between the IDCNS and KOA. These findings substantiate the genetic underpinnings supporting the association between the CNS and OA.

Osteoarthritis is a progressive, irreversible debilitating whole joint disease that affects millions of people worldwide. Despite the availability of various options (non-pharmacological and pharmacological treatments and therapy, orthobiologics, and surgical interventions), none of them can definitively cure osteoarthritis in patients. Strategies based on the controlled release of therapeutic compounds via biocompatible materials may provide powerful tools to enhance the spatiotemporal delivery, expression, and activities of the candidate agents as a means to durably manage the pathological progression of osteoarthritis in the affected joints upon convenient intra-articular (injectable) delivery while reducing their clearance, dissemination, or side effects. The goal of this review is to describe the current knowledge and advancements of controlled release to treat osteoarthritis, from basic principles to applications in vivo using therapeutic recombinant molecules and drugs and more innovatively gene sequences, providing a degree of confidence to manage the disease in patients in a close future.

Blood flow signals (BFSs) through the bone cortex on ultrasonography (US) and bone marrow lesions (BMLs) detected on magnetic resonance imaging (MRI) can be used to assess bone lesions; however, no studies have reported their relationship. Therefore, this study aimed to assess whether BFSs through the bone cortex on US can serve as a screening test for detecting BMLs on MRI in patients with early knee osteoarthritis (OA).

This study enrolled patients with knee joint pain who were diagnosed with early knee OA between January 2018 and January 2024. We targeted 77 patients who underwent MRI and in whom the presence or absence of BFSs through the bone cortex was confirmed on US. The association between BFSs and BMLs was evaluated using the chi-square test, and the sensitivity and specificity of BFSs for detecting BMLs on MRI were calculated.

The chi-square test showed that BFSs and BMLs were significantly associated in the femur and tibia (femur: χ2 [1] = 52.9, p < 0.001; Tibia: χ2 [1] = 44.8, p < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of BFSs for detecting BMLs on MRI were 85.0%, 96.5%, 89.5%, and 94.8%, respectively, for the femur, and 84.0%, 92.3%, 84.0%, and 92.3%, respectively, for the tibia.

BFSs through the bone cortex on US can be used as a screening test for detecting BMLs on MRI in patients with early knee OA.

The prototype of a biomimetic multi-spiked connecting scaffold (MSC-Scaffold) represents an essential innovation in the fixation in subchondral trabecular bone of components for a new generation of entirely cementless hip resurfacing arthroplasty (RA) endoprostheses. In designing such a functional biomaterial scaffold, identifying the microstructural and mechanical properties of the host bone compromised by degenerative disease is crucial for proper post-operative functioning and long-term maintenance of the endoprosthesis components. This study aimed to explore, depending on the occurrence of obesity, changes in the microstructure and mechanical properties of the subchondral trabecular bone in femoral heads of osteoarthritis (OA) patients caused by the MSC-Scaffold embedding. Computed microtomography (micro-CT) scanning of femoral heads from OA patients was conducted before and after the mechanical embedding of the MSC-Scaffold. Bone morphometric parameters such as bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) for regions surrounding the MSC-Scaffold were computed, and the mechanical properties such as bone density (ρB), bone compressive strength (S), and the Young's modulus (E) within these regions were calculated. A statistically significant increase in BV/TV (by 15.0% and 24.9%) and Tb.Th (by 13.1% and 42.5%) and a decrease in Tb.N (by 15.2% and 23.6%) were observed, which translates to an increase in ρB (by 15.0% and 24.9%), S (by 28.8% and 49.5%), and E (by 18.0% and 29.8%) in non-obese patients and obese patients, respectively. These changes in properties are favorable for the mechanical loads' transfer from the artificial joint surface via the MSC-Scaffold to the periarticular trabecular bone of the OA femoral head in the postoperative period.

Degenerative musculoskeletal diseases are a class of diseases related to the gradual structural and functional deterioration of muscles, joints, and bones, including osteoarthritis (OA), osteoporosis (OP), sarcopenia (SP), and intervertebral disc degeneration (IDD). As the proportion of aging people around the world increases, degenerative musculoskeletal diseases not only have a multifaceted impact on patients, but also impose a huge burden on the medical industry in various countries. Therefore, it is crucial to find key regulatory factors and potential therapeutic targets. Recent studies have shown that irisin plays an important role in degenerative musculoskeletal diseases, suggesting that it may become a key molecule in the prevention and treatment of degenerative diseases of the musculoskeletal system. Therefore, this review provides a comprehensive description of the release and basic functions of irisin, and summarizes the role of irisin in OA, OP, SP, and IDD from a cellular and tissue perspective, providing comprehensive basis for clinical application. In addition, we summarized the many roles of irisin as a key information molecule in bone-muscle-adipose crosstalk and a regulatory molecule involved in inflammation, senescence, and cell death, and proposed the interesting possibility of irisin in degenerative musculoskeletal diseases.

Early diagnosis of post-traumatic osteoarthritis (PTOA) is critical for designing better treatments before the degradation becomes irreversible. We utilized multimodal high-resolution imaging to investigate early-stage deterioration in articular cartilage and the subchondral bone plate from a sub-critical impact to the knee joint, which initiates PTOA. The knee joints of 12 adult rabbits were mechanically impacted once on the femoral articular surface to initiate deterioration. At 2- and 14-week post-impact surgery, cartilage-bone blocks were harvested from the impact region in the animals (N = 6 each). These blocks were assessed for deterioration using polarized light microscopy (PLM), microcomputed tomography (μCT), and biochemical analysis. Statistically significant changes were noted in the impact tissues across the calcified zone (CZ) at 14 weeks post-impact: the optical retardation values in the CZ of impact cartilage had a drop of 29.0% at 14 weeks, while the calcium concentration in the CZ of impact cartilage also had a significant drop at 14 weeks. A significant reduction of 6.3% in bone mineral density (BMD) was noted in the subchondral bone plate of the impact samples at 14 weeks. At 2 weeks post-impact, only minor, non-significant changes were measured. Furthermore, the impact knees after 14 weeks had greater structural changes compared with the 2-week impact knees, indicating progressive degradation over time. The findings of this study facilitated a connection between mineralization alterations and the early deterioration of knee cartilage after a mechanical injury. In a broader context, these findings can be beneficial in improving clinical strategies to manage joint injuries.

Posttraumatic osteoarthritis (PTOA) commonly develops following anterior cruciate ligament (ACL) injuries, affecting around 50% of individuals within 10-20 years. Recent studies have highlighted early changes in subchondral bone structure after ACL injury in adolescent or young adult mice, which could contribute to the development of PTOA. However, ACL injuries do not only occur early in life. Middle-aged and older patients also experience ACL injuries and PTOA, but whether the aged subchondral bone also responds rapidly to injury is unknown. This study utilized a noninvasive, single overload mouse injury model to assess subchondral bone microarchitecture, turnover, and material properties in both young adults (5 months) and early old age (22 months) female C57BL/6JN mice at 7 days after injury. Mice underwent either joint injury (i.e., produces ACL tears) or sham injury procedures on both the loaded and contralateral limbs, allowing evaluation of the impacts of injury versus loading. The subchondral bone response to ACL injury is distinct for young adult and aged mice. While 5-month mice show subchondral bone loss and increased bone resorption postinjury, 22-month mice did not show loss of bone structure and had lower bone resorption. Subchondral bone plate modulus increased with age, but not with injury. Both ages of mice showed several bone measures were altered in the contralateral limb, demonstrating the systemic skeletal response to joint injury. These data motivate further investigation to discern how osteochondral tissues differently respond to injury in aging, such that diagnostics and treatments can be refined for these demographics.

Low-dose aspirin is widely used as a preventive medication for cardiovascular diseases. However, there is controversy regarding the impact of low-dose aspirin on articular cartilage. The aim of this study is to explore the association between low-dose aspirin intake and osteoarthritis (OA).

We conducted a cross-sectional study based on the United States population data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. The investigation of low-dose aspirin intake and the diagnosis of OA was based on self-reporting in questionnaires. Multivariate regression models was used to assess the relationship between low-dose aspirin intake and OA. In addition, subgroup and interaction analysis were performed to assess the robustness of the results.

A total of 12,215 participants were included in this study. Multivariate logistic regression analysis showed that low-dose aspirin use had significantly increased the odds of OA (OR = 1.14; 95% CI: 1.01-1.28; p = 0.035). A significant and consistent association of low-dose aspirin intake with OA was still observed in each subgroup stratified by gender, age, and the presence of comorbidities including diabetes, coronary heart disease, hypertension, and stroke. The results illustrated that the relationship between low-dose aspirin intake and OA was stable in all subgroups and had no interaction.

Our study confirmed that low-dose aspirin intake may increase the risk of OA. Attention should be paid to the possibility of joint degenerative changes in patients who take low-dose aspirin chronically. However, further studies are needed to explore the possible mechanisms behind this association.

To categorize the temporal progression of subchondral bone alterations induced by compromising meniscus integrity in mouse and rat models of knee osteoarthritis (OA).

Scoping review of investigations reporting subchondral bone changes with appropriate negative controls in the different mouse and rat models of OA induced by compromising meniscus integrity.

The available literature provides appropriate temporal detail on subchondral changes in these models, covering the entire spectrum of OA with an emphasis on early and mid-term time points. Microstructural changes of the subarticular spongiosa are comprehensively described; those of the subchondral bone plate are not. In mouse models, global subchondral bone alterations are unidirectional, involving an advancing sclerosis of the trabecular structure over time. In rats, biphasic subchondral bone alterations begin with an osteopenic degeneration and loss of subchondral trabeculae, progressing to a late sclerosis of the entire subchondral bone. Rat models, independently from the applied technique, relatively faithfully mirror the early bone loss detected in larger animals, and the late subchondral bone sclerosis observed in human advanced OA.

Mice and rats allow us to study the microstructural consequences of compromising meniscus integrity at high temporal detail. Thickening of the subchondral bone plate, an early loss of thinner subarticular trabecular elements, followed by a subsequent sclerosis of the entire subchondral bone are all important and reliable hallmarks that occur in parallel with the advancing articular cartilage degeneration. Thoughtful decisions on the study design, laterality, selection of controls and volumes of interest are crucial to obtain meaningful data.

Treating bone-cartilage defects is a fundamental clinical problem. The ability of damaged cartilage to self-repair is limited due to its avascularity. Left untreated, these defects can lead to osteoarthritis. Details of osteochondral defect repair are elusive, but animal models indicate healing occurs via an endochondral ossification-like process, similar to that in the growth plate. In the growth plate, the signalling molecules parathyroid hormone-related protein (PTHrP) and Indian Hedgehog (Ihh) form a feedback loop regulating chondrocyte hypertrophy, with Ihh inducing and PTHrP suppressing hypertrophy. To better understand this repair process and to explore the regulatory role of signalling molecules on the regeneration process, we formulate a reaction-diffusion mathematical model of osteochondral defect regeneration after chondrocyte implantation. The drivers of healing are assumed to be chondrocytes and osteoblasts, and their interaction via signalling molecules. We model cell proliferation, migration and chondrocyte hypertrophy, and matrix production and conversion, spatially and temporally. We further model nutrient and signalling molecule diffusion and their interaction with the cells. We consider the PTHrP-Ihh feedback loop as the backbone mechanisms but the model is flexible to incorporate extra signalling mechanisms if needed. Our mathematical model is able to represent repair of osteochondral defects, starting with cartilage formation throughout the defect. This is followed by chondrocyte hypertrophy, matrix calcification and bone formation deep inside the defect, while cartilage at the surface is maintained and eventually separated from the deeper bone by a thin layer of calcified cartilage. The complete process requires around 48 months. A key highlight of the model demonstrates that the PTHrP-Ihh loop alone is insufficient and an extra mechanism is required to initiate chondrocyte hypertrophy, represented by a critical cartilage density. A parameter sensitivity study reveals that the timing of the repair process crucially depends on parameters, such as the critical cartilage density, and those describing the actions of PTHrP to suppress hypertrophy, such as its diffusion coefficient, threshold concentration and degradation rate.

Guideline-based surgical cartilage therapy for focal cartilage damage offers highly effective possibilities to sustainably reduce patients' complaints and to prevent or at least delay the development of early osteoarthritis. In the knee joint, it has the potential to reduce almost a quarter of the arthroses requiring joint replacement caused by cartilage damage. Biologically effective injection therapies could further improve these results. Based on the currently available literature and preclinical studies, intra- and postoperative injectables may have a positive effect of platelet-rich plasma/fibrin (PRP/PRF) and hyaluronic acid (HA) on cartilage regeneration and, in the case of HA injections, also on the clinical outcome can be assumed. The role of a combination therapy with use of intra-articular corticosteroids is lacking in the absence of adequate study data and cannot be defined yet. With regard to adipose tissue-based cell therapy, the current scientific data do not yet justify any recommendation for its use. Further studies also regarding application intervals, timing and differences in different joints are required.

Osteoarthritis is a debilitating chronic joint disorder that affects millions of people worldwide. Since palliative and surgical treatments cannot completely regenerate hyaline cartilage within the articulating joint, osteochondral (OC) tissue engineering has been explored to heal OC defects. Utilizing computational simulations and three-dimensional (3D) printing, we aimed to build rationale around fabricating OC scaffolds with enhanced biomechanics. First, computational simulations revealed that interfacial fibrils within a bilayer alter OC scaffold deformation patterns by redirecting load-induced stresses toward the top of the cartilage layer. Principal component analysis revealed that scaffolds with 800 μm long fibrils (scaffolds 8A-8H) possessed optimal biomechanical properties to withstand compression and shear forces. While compression testing indicated that OC scaffolds with 800 μm fibrils did not have greater compressive moduli than other scaffolds, interfacial shear tests indicated that scaffold 8H possessed the greatest shear strength. Lastly, failure analysis demonstrated that yielding or buckling models describe interfacial fibril failure depending on fibril slenderness S. Specifically for scaffolds with packing density n = 6 and n = 8, the yielding failure model fits experimental loads with S < 10, while the buckling model fitted scaffolds with S < 10 slenderness. The research presented provides critical insights into designing 3D printed interfacial scaffolds with refined biomechanics toward improving OC tissue engineering outcomes.

When dealing with the health status of the knee articular surface, the entire osteochondral unit has gained increasing attention, and in particular the subchondral bone, which plays a key role in the integrity of the osteochondral unit. The aim of this article was to discuss the current evidence on the role of the subchondral bone.

Experts from different geographical regions were involved in performing a review on highly discussed topics about the subchondral bone, ranging from its etiopathogenetic role in joint degeneration processes to its prognostic role in chondral and osteochondral defects, up to treatment strategies to address both the subchondral bone and the articular surface.

Subchondral bone has a central role both from an aetiologic point of view and as a diagnostic tool, and its status was found to be relevant also as a prognostic factor in the follow-up of chondral treatment. Finally, the recognition of its importance in the natural history of these lesions led to consider subchondral bone as a treatment target, with the development of osteochondral scaffolds and procedures to specifically address osteochondral lesions.

Subchondral bone plays a central role in articular surface lesions from different points of view. Several aspects still need to be understood, but a growing interest in subchondral bone is to be expected in the upcoming future towards the optimization of joint preservation strategies.

Level V, expert opinion.

In the realm of studying joint-related diseases, there is a continuous quest for more accurate and representative models. Recently, regenerative medicine and tissue engineering have seen a growing interest in utilizing organoids as powerful tools for studying complex biological systems in vitro. Organoids, three-dimensional structures replicating the architecture and function of organs, provide a unique platform for investigating disease mechanisms, drug responses, and tissue regeneration. The surge in organoid research is fueled by the need for physiologically relevant models to bridge the gap between traditional cell cultures and in vivo studies. Osteochondral organoids have emerged as a promising avenue in this pursuit, offering a better platform to mimic the intricate biological interactions within bone and cartilage. This review explores the significance of osteochondral organoids and the need for their development in advancing our understanding and treatment of bone and cartilage-related diseases. It summarizes osteochondral organoids' insights and research progress, focusing on their composition, materials, cell sources, and cultivation methods, as well as the concept of organoids on chips and application scenarios. Additionally, we address the limitations and challenges these organoids face, emphasizing the necessity for further research to overcome these obstacles and facilitate orthopedic regeneration.

The subchondral bone is an emerging regulator of osteoarthritis (OA). However, knowledge of how specific subchondral alterations relate to cartilage degeneration remains incomplete.

Femoral heads were obtained from 44 patients with primary OA during total hip arthroplasty and from 30 non-OA controls during autopsy. A multiscale assessment of the central subchondral bone region comprising histomorphometry, quantitative backscattered electron imaging, nanoindentation, and osteocyte lacunocanalicular network characterization was employed.

In hip OA, thickening of the subchondral bone coincided with a higher number of osteoblasts (controls: 3.7 ± 4.5 mm-1, OA: 16.4 ± 10.2 mm-1, age-adjusted mean difference 10.5 mm-1 [95% CI 4.7 to 16.4], p < 0.001) but a similar number of osteoclasts compared to controls (p = 0.150). Furthermore, higher matrix mineralization heterogeneity (CaWidth, controls: 2.8 ± 0.2 wt%, OA: 3.1 ± 0.3 wt%, age-adjusted mean difference 0.2 wt% [95% CI 0.1 to 0.4], p = 0.011) and lower tissue hardness (controls: 0.69 ± 0.06 GPa, OA: 0.67 ± 0.06 GPa, age-adjusted mean difference -0.05 GPa [95% CI -0.09 to -0.01], p = 0.032) were detected. While no evidence of altered osteocytic perilacunar/canalicular remodeling in terms of fewer osteocyte canaliculi was found in OA, specimens with advanced cartilage degeneration showed a higher number of osteocyte canaliculi and larger lacunocanalicular network area compared to those with low-grade cartilage degeneration. Multiple linear regression models indicated that several subchondral bone properties, especially osteoblast and osteocyte parameters, were closely related to cartilage degeneration (R2 adjusted = 0.561, p < 0.001).

Subchondral bone properties in OA are affected at the compositional, mechanical, and cellular levels. Based on their strong interaction with cartilage degeneration, targeting osteoblasts/osteocytes may be a promising therapeutic OA approach.

All data are available in the main text or the supplementary materials.

Osteoarthritis (OA) is the most common joint disease, and good therapeutic results are often difficult to obtain due to its complex pathogenesis and diverse causative factors. After decades of research and exploration of OA, it has been progressively found that subchondral bone is essential for its pathogenesis, and pathological changes in subchondral bone can be observed even before cartilage lesions develop. Osteoclasts, the main cells regulating bone resorption, play a crucial role in the pathogenesis of subchondral bone. Subchondral osteoclasts regulate the homeostasis of subchondral bone through the secretion of degradative enzymes, immunomodulation, and cell signaling pathways. In OA, osteoclasts are overactivated by autophagy, ncRNAs, and Rankl/Rank/OPG signaling pathways. Excessive bone resorption disrupts the balance of bone remodeling, leading to increased subchondral bone loss, decreased bone mineral density and consequent structural damage to articular cartilage and joint pain. With increased understanding of bone biology and targeted therapies, researchers have found that the activity and function of subchondral osteoclasts are affected by multiple pathways. In this review, we summarize the roles and mechanisms of subchondral osteoclasts in OA, enumerate the latest advances in subchondral osteoclast-targeted therapy for OA, and look forward to the future trends of subchondral osteoclast-targeted therapies in clinical applications to fill the gaps in the current knowledge of OA treatment and to develop new therapeutic strategies.

Osteochondral defects are deep joint surface lesions that affect the articular cartilage and the underlying subchondral bone. In the current study, a tissue engineering approach encompassing individual cells encapsulated in a biocompatible hydrogel is explored in vitro and in vivo. Cell-laden hydrogels containing either human periosteum-derived progenitor cells (PDCs) or human induced pluripotent stem cell (iPSC)-derived chondrocytes encapsulated in gelatin methacryloyl (GelMA) were evaluated for their potential to regenerate the subchondral mineralized bone and the articular cartilage on the joint surface, respectively. PDCs are easily isolated and expanded progenitor cells that are capable of generating mineralized cartilage and bone tissue in vivo via endochondral ossification. iPSC-derived chondrocytes are an unlimited source of stable and highly metabolically active chondrocytes. Cell-laden hydrogel constructs were cultured for up to 28 days in a serum-free chemically defined chondrogenic medium. On day 1 and day 21 of the differentiation period, the cell-laden constructs were implanted subcutaneously in nude mice to evaluate ectopic tissue formation 4 weeks post-implantation. Taken together, the data suggest that iPSC-derived chondrocytes encapsulated in GelMA can generate hyaline cartilage-like tissue constructs with different levels of maturity, while using periosteum-derived cells in the same construct type generates mineralized tissue and cortical bone in vivo. Therefore, the aforementioned cell-laden hydrogels can be an important part of a multi-component strategy for the manufacturing of an osteochondral implant.

Osteoarthritis (OA) is a degenerative bone disease associated with aging. The rising global aging population has led to a surge in OA cases, thereby imposing a significant socioeconomic burden. Researchers have been keenly investigating the mechanisms underlying OA. Previous studies have suggested that the disease starts with synovial inflammation and hyperplasia, advancing toward cartilage degradation. Ultimately, subchondral-bone collapse, sclerosis, and osteophyte formation occur. This progression is deemed as "top to bottom." However, recent research is challenging this perspective by indicating that initial changes occur in subchondral bone, precipitating cartilage breakdown. In this review, we elucidate the epidemiology of OA and present an in-depth overview of the subchondral bone's physiological state, functions, and the varied pathological shifts during OA progression. We also introduce the role of multifunctional signal pathways (including osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK), and chemokine (CXC motif) ligand 12 (CXCL12)/CXC motif chemokine receptor 4 (CXCR4)) in the pathology of subchondral bone and their role in the "bottom-up" progression of OA. Using vivid pattern maps and clinical images, this review highlights the crucial role of subchondral bone in driving OA progression, illuminating its interplay with the condition.

Osteoarthritis has become a major disease threatening human health. The mechanism of injury under fluid involvement can be studied by finite element method. However, most models only model the articular cartilage to study the subchondral bone structure, which is too simplistic. In this study, a complete osteochondral unit was modeled and provided with a poroelastic material, and as osteoarthritis develops and the size, thickness, and shape of the osteochondral unit defect varies, the fluid flow behavior is altered, which may have functional consequences that feed back into the progression of the injury. The results of the study showed that interstitial fluid pressure and velocity decreased in defective osteochondral units. This trend was exacerbated as the size and thickness of the defect in the osteochondral unit increased. When the defect reached the trabeculae, pressure around the cartilage defect in the osteochondral unit was greatest, flow velocity in the subchondral cortical bone was greatest, and pressure and flow velocity around the trabecular defect were lowest. As osteoarthritis develops, the osteochondral unit becomes more permeable, and the pressure of the interstitial fluid decreases while the flow rate increases, resulting in severe nutrient loss. This may be the fluid flow mechanism behind osteochondral defects and osteoarthritis.

To investigate whether concomitant autologous bone grafting adversely affects clinical outcome and graft survival after matrix-associated autologous chondrocyte implantation (M-ACI).

The present study examines registry data of patients who underwent M-ACI with or without autologous bone grafting for large-sized chondral or osteochondral defects. Propensity score matching was performed to exclude potential confounders. A total of 215 patients with similar baseline characteristics were identified. Clinical outcome was assessed at the time of surgery and at 6, 12, 24, 36 and 60 months using the Knee Injury and Osteoarthritis Outcome Score (KOOS). KOOS change, clinical response rate, KOOS subcomponents and failure rate were determined.

Patients treated with M-ACI and autologous bone grafting achieved comparable clinical outcomes compared with M-ACI alone. At 24 months postoperatively, the patient-reported outcome (PRO) of patients treated with M-ACI and autologous bone grafting was even significantly better as measured by KOOS (74.9 ± 18.8 vs. 79.2 ± 15.4; p = 0.043). However, the difference did not exceed the minimal clinically important difference (MCID). In patients with M-ACI and autologous bone grafting, a greater change in KOOS relative to baseline was observed at 6 (9.3 ± 14.7 vs. 15.0 ± 14.7; p = 0.004) and 12 months (12.6 ± 17.2 vs. 17.7 ± 14.6; p = 0.035). Overall, a high clinical response rate was observed in both groups at 24 months (75.8% vs. 82.0%; p = n.s.). The estimated survival at the endpoint of reoperation for any reason was 82.1% (SD 2.8) at 8.4 years for isolated M-ACI and 88.7% (SD 2.4) at 8.2 years for M-ACI with autologous bone grafting (p = 0.039).

Even in the challenging cohort of large osteochondral defects, the additional treatment with autologous bone grafting leads to remarkably good clinical outcomes in patients treated with M-ACI. In fact, they tend to benefit more from surgery, have lower revision rates and achieve clinical response rates earlier. Subchondral bone management is critical to the success of M-ACI and should be addressed in the treatment of borderline defects.

Level III.

Osteoarthritis (OA) is an incapacitating and one of the most common physically degenerative conditions with an assorted etiology and a highly complicated molecular mechanism that to date lacks an efficient treatment. The capacity to design biological networks and accurately modify existing genomic sites holds an apt potential for applications across medical and biotechnological sciences. One of these highly specific genomes editing technologies is the CRISPR/Cas9 mechanism, referred to as the clustered regularly interspaced short palindromic repeats, which is a defense mechanism constituted by CRISPR associated protein 9 (Cas9) directed by small non-coding RNAs (sncRNA) that bind to target DNA through Watson-Crick base pairing rules where subsequent repair of the target DNA is initiated. Up-to-date research has established the effectiveness of the CRISPR/Cas9 mechanism in targeting the genetic and epigenetic alterations in OA by suppressing or deleting gene expressions and eventually distributing distinctive anti-arthritic properties in both in vitro and in vivo osteoarthritic models. This review aims to epitomize the role of this high-throughput and multiplexed gene editing method as an analogous therapeutic strategy that could greatly facilitate the clinical development of OA-related treatments since it's reportedly an easy, minimally invasive technique, and a comparatively less painful method for osteoarthritic patients.

To determine the 50 most frequently cited studies on osteochondritis dissecans (OCD) and to conduct a bibliometric analysis of these studies.

We performed a search within the Clarivate Web of Science database, identifying articles published before December 2022 that encompass topics related to OCD. The search was conducted using the keywords "Osteochondritis Dissecans OR Osteochondritis OR Dissecans."Search results were then filtered using predetermined guidelines and criteria, and the 50 most-cited articles were selected for analysis. Extracted data included title, journal, design, main topic, joint, citations, year, country of origin, and level of evidence.

The search yielded 3,865 articles. The 50 most-cited articles were published between 1957 and 2018, with the greatest proportion published from 2000 to 2009 (60%). The most frequently studied topic was treatment (68%), followed by etiology (14%) and imaging (8%). The majority of articles had Level IV evidence (36%) and the largest proportion focused on the knee joint (36%), followed by the ankle (32%), and elbow (6%). The mean citation count per article was 287 (range: 157-1,050), with the most-cited articles primarily published from 2000 to 2003. The leading country of origin was the United States, accounting for 19 publications.

Most of the top 50 most-cited articles regarding OCD are about treatment, and the knee is the most-studied joint. The majority of the articles were Level IV evidence and were published in the United States between 2000 and 2009.

The top 50 most-cited studies list will provide researchers, medical students, residents, and fellows with a foundational list of the most important and influential academic contributions regarding osteochondritis dissecans (OCD).

Tagetes erecta and Ocimum basilicum are medicinal plants that exhibit anti-inflammatory effects against various diseases. However, their individual and combined effects on osteoarthritis (OA) are unknown. Herein, we aimed to demonstrate the effects of T. erecta, O. basilicum, and their mixture, WGA-M001, on OA pathogenesis. The administration of total extracts of T. erecta and O. basilicum reduced cartilage degradation and inflammation without causing cytotoxicity. Although WGA-M001 contained lower concentrations of the individual extracts, it strongly inhibited the expression of pathogenic factors. In vivo OA studies also supported that WGA-M001 had protective effects against cartilage destruction at lower doses than those of T. erecta and O. basilicum. Moreover, its effects were stronger than those observed using Boswellia and Perna canaliculus. WGA-M001 effectively inhibited the interleukin (IL)-1β-induced nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway and ERK phosphorylation. Furthermore, RNA-sequence analysis also showed that WGA-M001 decreased the expression of genes related to the IL-1β-induced NF-κB and ERK signaling pathways. Therefore, WGA-M001 is more effective than the single total extracts of T. erecta and O. basilicum in attenuating OA progression by regulating ERK and NF-κB signaling. Our results open new possibilities for WGA-M001 as a potential therapeutic agent for OA treatment.