Site-specific elastic and viscoelastic biomechanical properties of healthy and osteoarthritic human knee joint articular cartilage.

Articular cartilage exhibits site-specific biomechanical properties. However, no study has comprehensively characterized site-specific cartilage properties from the same knee joints at different stages of osteoarthritis (OA). Cylindrical osteochondral explants (n = 381) were harvested from donor-matched lateral and medial tibia, lateral and medial femur, patella, and trochlea of cadaveric knees (N = 17). Indentation test was used to measure the elastic and viscoelastic mechanical properties of the samples, and Osteoarthritis Research Society International (OARSI) grading system was used to categorize the samples into normal (OARSI 0-1), early OA (OARSI 2-3), and advanced OA (OARSI 4-5) groups. OA-related changes in cartilage mechanical properties were site-specific. In the lateral and medial tibia and trochlea sites, equilibrium, instantaneous and dynamic moduli were higher (p < 0.001) in normal tissue than in early and advanced OA tissue. In lateral and medial femur, equilibrium, instantaneous and dynamic moduli were smaller in advanced OA, but not in early OA, than in normal tissue. The phase difference (0.1-0.25 Hz) between stress and strain was significantly smaller (p < 0.05) in advanced OA than in normal tissue across all sites except medial tibia. Our results indicated that in contrast to femoral and patellar cartilage, equilibrium, instantaneous and dynamic moduli of the tibia and trochlear cartilage decreased in early OA. These may suggest that the tibia and trochlear cartilage degrades faster than the femoral and patellar cartilage. The information is relevant for developing site-specific computational models and engineered cartilage constructs.

Chronic ACLD Knees with Early Developmental Cartilage Lesions Exhibited Increased Posterior Tibial Translation during Level Walking.

OBJECTIVE: Early articular cartilage lesion (CL) is a vital sign in the onset of posttraumatic knee osteoarthritis (PTOA) in patients with anterior cruciate ligament deficiency (ACLD). Researchers have suggested that altered kinematics could accelerate CLs and, therefore, lead to the onset of PTOA. However, little is known about whether specific knee kinematics exist that lead to early CL in chronic ACLD knees. Level walking is the most frequent and relevant in vivo activity, which greatly impacts knee health. We hypothesized that the knee kinematics during level walking in chronic ACLD knees with early tibiofemoral CL would significantly differ from those of chronic ACLD knees without early tibiofemoral CL. METHODS: Thirty patients with a chronic ACLD history, including 18 subjects with CLs and 12 subjects without CLs, and 35 healthy control subjects were recruited for the study from July 2020 to August 2022. The knee kinematic data during level walking were collected using a three-dimensional motion analysis system. The kinematic differences between groups were compared using statistical parametric mapping with one dimension for One-Way ANOVA. The cartilage statuses of the ACLD knees were assessed via MRI examination. The CLs distribution of subjects was evaluated using a modified Noyes scale and analyzed by chi-square tests. RESULTS: ACLD knees with CLs had significantly greater posterior tibial translation (7.7-8.0mm, 12%-18% gait cycle GC, p = 0.014) compared to ACLD knees without CLs during level walking. ACLD knees with CLs had greater posterior tibial translation (4.6-5.5mm, 0%-23% GC, p < 0.001; 5.8-8.0mm, 86%-100% GC, p < 0.001) than healthy controls during level walking. In the group of ACLD knees with CLs, CL is mainly located in the back of the tibia plateau and front of load bearing area of the medial femoral condyle (p < 0.05). CONCLUSION: Chronic anterior cruciate ligament deficient knees with cartilage lesions have increased posterior tibial translation compared to anterior cruciate ligament deficient knees without cartilage lesions and healthy subjects. The posterior tibial translation may play an important role in knee cartilage degeneration in ACLD knees. The increased posterior tibial translation and cartilage lesion characteristics may improve our understanding of the role of knee kinematics in cartilage degeneration and could be a helpful potential reference for anterior cruciate ligament deficient therapy, such as physical training to improve abnormal kinematic behavior.

CD38 Drives Progress of Osteoarthritis by Affecting Cartilage Homeostasis.

OBJECTIVE: To observe expression of CD38, a key modulator of nicotinamide dinucleotide (NAD+) metabolism in mice with knee osteoarthritis, and protective effect of CD38 inhibition during the osteoarthritis (OA) development. METHOD: The destabilization of the medial meniscus (DMM) model was performed in mice to mimic the process of OA. Immunofluorescence of CD38 was performed to evaluate its response during the OA process. Limb bud-derived mesenchymal cells were isolated for micromass culture. 100 nM or 1 µM CD38 inhibitor (78c) treatment for 14 days and CD38 sgRNA infection were then used to explore the effects of chondrogenic differentiation via Alcian blue staining. The expressions of chondrogenic markers were detected using RT-PCR and Western blot. To explore the protective effect of CD38 inhibitor on cartilage degradation during OA in vivo, a CD38 inhibitor was injected into the knee joint after DMM operations. Micro-CT analysis and Safranin O-fast green staining were used to evaluate subchondral bone micro-architecture changes and cartilage degeneration. RESULTS: Compared to the control group, the CD38 expression in superficial cartilage was obviously increased in DMM group (P < 0.05). During the normal chondrogenic differentiation, the extracellular matrix formed and expression of Sox9, Col2, aggrecan increased apparently while CD38 expression decreased, which could be reversed with ablation of CD38 in limb bud-derived mesenchymal cells. Consistent with findings in vitro, CD38 blockage via CD38 inhibitor injection protected against osteosclerosis in medial subchondral bone and cartilage degeneration in DMM-induced experimental mice. Compared to the Sham group, DMM mice showed significantly increased values of BV and BV/TV in subchondral bone (P < 0.05) and Mankin score, which could be rescued by 78c treatment (P < 0.05). Also the CD38 inhibitor contributed to homeostasis of anabolism and catabolism by upregulating Sox9, Col2, aggrecan and downregulating Runx2, Col10 and Mmp13. CONCLUSION: This study primarily implicates CD38 as an important regulator of chondrogenic differentiation. Inhibition of CD38 demonstrated protection against cartilage degeneration, which suggests that CD38 could be a potential therapeutic target for OA.

Post-traumatic Osteoarthritis in Rabbits Following Traumatic Injury and Surgical Reconstruction of the Knee.

Post-traumatic osteoarthritis (PTOA) of the knee is often attributed to anterior cruciate ligament (ACL) and meniscus injury. The development of PTOA, however, does not seem to depend on whether or not the damaged ACL is reconstructed. There has been a need to develop animal models to study the mechanisms of PTOA following reconstruction of a traumatized knee. Eighteen rabbits underwent closed-joint trauma to produce ACL rupture and meniscus damage. Then, for the first time, the traumatized knee was surgically repaired in this animal model. Upon euthanasia at 1-, 3- or 6-month post-trauma, joint stability, cartilage morphology and mechanical properties, as well as histology of the cartilage and subchondral bone were evaluated. Trauma-induced knee injury involved 72% mid-substance ACL rupture, 28% partial ACL tear and 56% concurrent medial meniscal damage. ACL reconstruction effectively restored joint stability by reducing joint laxity to a level similar to that in the contralateral intact knee. Compared to their contralateral controls, reconstructed limbs showed osteoarthritic changes to the cartilage and subchondral bone as early as 1-month post-trauma. The degeneration progressed over time up to 6-month. Overall, the medial compartments had more tissue damage than their corresponding lateral counterparts. Damage patterns to the ACL, the frequency of observed concurrent meniscal injury, and reductions in cartilage integrity and health were consistent with clinical observations of human patients who undergo ACL injury and reconstruction. Thus, we believe the combined closed-joint injury and surgical repair lapine model of PTOA, being first-ever and clinically relevant, shows promise to evaluate well-targeted therapeutics and other interventions for this chronic disease.

Effects of Immobilization and Swimming on the Progression of Osteoarthritis in Mice.

Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration of articular cartilage and thickening and sclerosis of the subchondral bone. Mechanical factors play significant roles in the development and progression of OA, but it is still controversial whether exercise or rest is a more effective treatment for OA patients. In this study, we compared the effects of swimming and immobilization at different stages of OA in mice. Four weeks (the middle stage of OA) or eight weeks (the late stage of OA) after DMM (destabilization of the medial meniscus) surgery, the mice were subjected to four-week immobilization or swimming. Ink blot analysis and a beam walking test were performed to measure the gait and balance ability. Histological analysis was performed to determine the trabecular bone area, the thickness of subchondral bone, the thickness of the cartilage, the OARSI score, and the expression of MMP13 (matrix metalloproteinases) and IL-6 (interleukin). The results showed that at the middle stage of OA, both immobilization and swimming slowed down the progression of OA. Immobilization relieved OA to a certain extent by decreasing the production of regulatory factors to attenuate the degeneration of cartilage, which partly relieved the effects of DMM on gait, mainly in the hindlimb. Swimming mainly attenuated the thickening and rescued the area of subchondral bone.

Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage.

INTRODUCTION: A disintegrin and metalloproteinase 17 (Adam17), also known as TNFα-converting enzyme (Tace), is a membrane-anchored protein involved in shedding of TNF, IL-6 receptor, ligands of epidermal growth factor receptor (EGFR), and Notch receptor. This study aimed to examine the role of Adam17 in adult articular cartilage and osteoarthritis (OA) pathophysiology. MATERIALS AND METHODS: Adam17 expression was examined in mouse knee joints during OA development. We analyzed OA development in tamoxifen-inducible chondrocyte-specific Adam17 knockout mice of a resection of the medial meniscus and medial collateral ligament (medial) model, destabilization of the medial meniscus (DMM) model, and aging model. We analyzed downstream pathways by in vitro experiments, and further performed intra-articular administration of an Adam17 inhibitor TAPI-0 for surgically induced mouse OA. RESULTS: Adam17 expression in mouse articular cartilage was increased by OA progression. In all models, Adam17 knockout mice showed ameliorated progression of articular cartilage degradation. Adam17 knockout decreased matrix metallopeptidase 13 (Mmp13) expression in both in vivo and in vitro experiments, whereas Adam17 activation by phorbol-12-myristate-13-acetate (PMA) increased Mmp13 and decreased aggrecan in mouse primary chondrocytes. Adam17 activation enhanced release of soluble TNF and transforming growth factor alpha, a representative EGF ligand, from mouse primary chondrocytes, while it did not change release of soluble IL-6 receptor or nuclear translocation of Notch1 intercellular domain. Intra-articular administration of the Adam17 inhibitor ameliorated OA progression. CONCLUSIONS: This study demonstrates regulation of OA development by Adam17, involvement of EGFR and TNF pathways, and the possibility of Adam17 as a therapeutic target for OA.

Deformation behaviors and mechanical impairments of tissue cracks in immature and mature cartilages.

Degeneration of articular cartilage is often triggered by a small tissue crack. As cartilage structure and composition change with age, the mechanics of cracked cartilage may depend on the tissue age, but this relationship is poorly understood. Here, we investigated cartilage mechanics and crack deformation in immature and mature cartilage exposed to a full-thickness tissue crack using indentation testing and histology, respectively. When a cut was introduced, tissue cracks opened wider in the mature cartilage compared to the immature cartilage. However, the opposite occurred upon mechanical indentation over the cracked region. Functionally, the immature-cracked cartilages stress-relaxed faster, experienced increased tissue strain, and had reduced instantaneous stiffness, compared to the mature-cracked cartilages. Taken together, mature cartilage appears to withstand surface cracks and maintains its mechanical properties better than immature cartilage and these superior properties can be explained by the structure of their collagen fibrous network.

Characterisation of Growth Plate Dynamics in Murine Models of Osteoarthritis.

The purpose of this study was to investigate growth plate dynamics in surgical and loading murine models of osteoarthritis, to understand whether abnormalities in these dynamics are associated with osteoarthritis development. 8-week-old C57BL/6 male mice underwent destabilisation of medial meniscus (DMM) (n = 8) surgery in right knee joints. Contralateral left knee joints had no intervention (controls). In 16-week-old C57BL/6 male mice (n = 6), osteoarthritis was induced using non-invasive mechanical loading of right knee joints with peak force of 11N. Non-loaded left knee joints were internal controls. Chondrocyte transiency in tibial articular cartilage and growth plate was confirmed by histology and immunohistochemistry. Tibial subchondral bone parameters were measured using microCT and correlated to 3-dimensional (3D) growth plate bridging analysis. Higher expression of chondrocyte hypertrophy markers; Col10a1 and MMP13 were observed in tibial articular cartilage chondrocytes of DMM and loaded mice. In tibial growth plate, Col10a1 and MMP13 expressions were widely expressed in a significantly enlarged zone of proliferative and hypertrophic chondrocytes in DMM (p=0.002 and p<0.0001, respectively) and loaded (both p<0.0001) tibiae of mice compared to their controls. 3D quantification revealed enriched growth plate bridging and higher bridge densities in medial compared to lateral tibiae of DMM and loaded knee joints of the mice. Growth plate dynamics were associated with increased subchondral bone volume fraction (BV/TV; %) in medial tibiae of DMM and loaded knee joints and epiphyseal trabecular bone volume fraction in medial tibiae of loaded knee joints. The results confirm articular cartilage chondrocyte transiency in a surgical and loaded murine models of osteoarthritis. Herein, we reveal spatial variation of growth plate bridging in surgical and loaded osteoarthritis models and how these may contribute to anatomical variation in vulnerability of osteoarthritis development.

HA-g-CS Implant and Moderate-intensity Exercise Stimulate Subchondral Bone Remodeling and Promote Repair of Osteochondral Defects in Mice.

Background: Substantial evidence shows that crosstalk between cartilage and subchondral bone may play an important role in cartilage repair. Animal models have shown that hydroxyapatite-grafted-chitosan implant (HA-g-CS) and moderate-intensity exercise promote regeneration of osteochondral defects. However, no in vivo studies have demonstrated that these two factors may have a synergistic activity to facilitate subchondral bone remodeling in mice, thus supporting bone-cartilage repair. Questions: This study was to clarify whether HA-g-CS and moderate-intensity exercise might have a synergistic effect on facilitating (1) regeneration of osteochondral defects and (2) subchondral bone remodeling in a mouse model of osteochondral defects. Methods: Mouse models of osteochondral defects were created and divided into four groups. BC Group was subjected to no treatment, HC Group to HA-g-CS implantation into osteochondral defects, ME group to moderate-intensity treadmill running exercise, and HC+ME group to both HA-g-CS implantation and moderate-intensity exercise until sacrifice. Extent of subchondral bone remodeling at the injury site and subsequent cartilage repair were assessed at 4 weeks after surgery. Results: Compared with BC group, HC, ME and HC+ME groups showed more cartilage repair and thicker articular cartilage layers and HC+ME group acquired the best results. The extent of cartilage repair was correlated positively to bone formation activity at the injured site as verified by microCT and correlation analysis. Histology and immunofluorescence staining confirmed that bone remodeling activity was increased in HC and ME groups, and especially in HC+ME group. This bone formation process was accompanied by an increase in osteogenesis and chondrogenesis factors at the injury site which promoted cartilage repair. Conclusions: In a mouse model of osteochondral repair, HA-g-CS implant and moderate-intensity exercise may have a synergistic effect on improving osteochondral repair potentially through promotion of subchondral bone remodeling and generation of osteogenesis and chondrogenesis factors. Clinical Relevance: Combination of HA-g-CS implantation and moderate-intensity exercise may be considered potentially in clinic to promote osteochondral defect repair. Also, cartilage and subchondral bone forms a functional unit in an articular joint and subchondral bone may regulate cartilage repair by secreting growth factors in its remodeling process. However, a deeper insight into the exact role of HA-g-CS implantation and moderate-intensity exercise in promoting osteochondral repair in other animal models should be explored before they can be applied in clinic in the future.

Biomechanics of the Femoral Head Cartilage and Subchondral Trabecular Bone in Osteoporotic and Osteopenic Fractures.

This study aimed to investigate the relationship between the micro structural properties of the subchondral trabecular bone (STB) and the macro mechanical properties of the articular cartilage (AC) in patients with osteoporotic (OP) and osteopenic (OPE) fractures. Sixteen femoral head samples (OP;OPE, n = 8 each) were obtained from female patients who underwent hip hemiarthroplasty. STB and AC specimens were harvested from those heads. Bone specimens were scanned using µ-CT to determine the micro structural properties. In-situ nondestructive compressive tests were performed for the cartilages to obtain elastic properties. The finite element technique was implemented on STB models created from µ-CT data to compute apparent elastic modulus. In addition, dynamic cyclic destructive tests were performed on STB and AC specimens to assess failure cycles. The results demonstrated that STB specimens in OPE group have more interconnected structure and higher cyclic dynamic strength than those in OP group. Furthermore, bone mineral density, failure cycle, and trabecular number of STB were positively correlated with the cartilage failure cycle, which indicates that STB alteration may affect the macroscopic mechanical properties of AC. The findings suggest that STB loss correlates with a decrease in cartilage strength and that improving of bone quality may prevent cartilage weakness.

Elastic, Dynamic Viscoelastic and Model-Derived Fibril-Reinforced Poroelastic Mechanical Properties of Normal and Osteoarthritic Human Femoral Condyle Cartilage.

Osteoarthritis (OA) degrades articular cartilage and weakens its function. Modern fibril-reinforced poroelastic (FRPE) computational models can distinguish the mechanical properties of main cartilage constituents, namely collagen, proteoglycans, and fluid, thus, they can precisely characterize the complex mechanical behavior of the tissue. However, these properties are not known for human femoral condyle cartilage. Therefore, we aimed to characterize them from human subjects undergoing knee replacement and from deceased donors without known OA. Multi-step stress-relaxation measurements coupled with sample-specific finite element analyses were conducted to obtain the FRPE material properties. Samples were graded using OARSI scoring to determine the severity of histopathological cartilage degradation. The results suggest that alterations in the FRPE properties are not evident in the moderate stages of cartilage degradation (OARSI 2-3) as compared with normal tissue (OARSI 0-1). Drastic deterioration of the FRPE properties was observed in severely degraded cartilage (OARSI 4). We also found that the FRPE properties of femoral condyle cartilage related to the collagen network (initial fibril-network modulus) and proteoglycan matrix (non-fibrillar matrix modulus) were greater compared to tibial and patellar cartilage in OA. These findings may inform cartilage tissue-engineering efforts and help to improve the accuracy of cartilage representations in computational knee joint models.

T1rho mapping of cartilage and menisci in patients with hyperuricaemia at 3 T: a preliminary study.

AIM: To compare and assess T1rho values of the femorotibial cartilage compartments and subregional menisci in patients with hyperuricaemia at 3 T. MATERIALS AND METHODS: Thirty-two patients were enrolled in the study and were subdivided into two subgroups: 15 healthy controls (three women, 12 men; mean age = 45.3 ± 10.9 years, age range 25-72 years) and 17 patients with asymptomatic hyperuricaemia (two women, 15 men; mean age = 44.4 ± 12.7 years, age range 26-77 years). All patients were evaluated using 3 T magnetic resonance imaging (MRI) using an eight-channel phased-array knee coil (transmit-receive). Wilcoxon's rank sum test and analysis of covariance (ANCOVA) were conducted to determine whether there were any statistically significant differences in the T1rho values of the femorotibial cartilage compartments and subregional menisci between the two subgroups. RESULTS: Lateral tibial cartilage (45.8 ± 2.9 ms) in the healthy subgroup had significantly lower (p<0.05) T1rho values than those of all subcompartments of the femorotibial cartilage in the hyperuricaemia subgroup. The lateral femoral cartilage (LF) in hyperuricaemia (54.6 ± 3.9 ms) subgroup had significantly higher (p<0.05) T1rho values than those of all subcompartments of the femorotibial cartilage except the LF in the healthy subgroup. Significantly higher (p<0.05) T1rho values existed in the LF of the healthy (54.6 ± 4.7 ms) subgroup in comparison with those of all subcompartments of femorotibial cartilage except the LF in hyperuricaemia subgroup. CONCLUSIONS: T1rho values in certain compartments of the femorotibial cartilage in patients with hyperuricaemia are elevated compared to those in healthy patients presumably due to reduced proteoglycan content, to which particular attention should be paid when diagnosing and treating the patients with hyperuricaemia in a clinical setting.

Relaxation capacity of cartilage is a critical factor in rate- and integrity-dependent fracture.

Articular cartilage heals poorly but experiences mechanically induced damage across a broad range of loading rates and matrix integrity. Because loading rates and matrix integrity affect cartilage mechanical responses due to poroviscoelastic relaxation mechanisms, their effects on cartilage failure are important for assessing and preventing failure. This paper investigated rate- and integrity-dependent crack nucleation in cartilage from pre- to post-relaxation timescales. Rate-dependent crack nucleation and relaxation responses were obtained as a function of matrix integrity through microindentation. Total work for crack nucleation increased with decreased matrix integrity, and with decreased loading rates. Critical energy release rate of intact cartilage was estimated as 2.39 ± 1.39 to 2.48 ± 1.26 kJ m-2 in a pre-relaxation timescale. These findings showed that crack nucleation is delayed when cartilage can accommodate localized loading through poroviscoelastic relaxation mechanisms before fracture at a given loading rate and integrity state.

Acute Talar Cartilage Deformation in Those with and without Chronic Ankle Instability.

PURPOSE: This study aimed 1) to determine whether talar cartilage deformation measured via ultrasonography (US) after standing and hopping loading protocols differs between chronic ankle instability (CAI) patients and healthy controls and 2) to determine whether the US measurement of cartilage deformation reflects viscoelasticity between standing and hopping protocols. METHODS: A total of 30 CAI and 30 controls participated. After a 60-min off-loading period, US images of the talar cartilage were acquired before and after static (2-min single-leg standing) and dynamic (60 single-leg forward hops) loading conditions. We calculated cartilage deformation by assessing the change in average thickness (mm) for overall, medial, and lateral talar cartilage. The independent variables include time (Pre60 and postloading), condition (standing and dynamic loading), and group (CAI and control). A three-way mixed-model repeated-measures ANCOVA and appropriate post hoc tests were used to compare cartilage deformation between the groups after static and dynamic loading. RESULTS: After the static loading condition, those with CAI had greater talar cartilage deformation compared with healthy individuals for overall (-10.87% vs -6.84%, P = 0.032) and medial (-12.98% vs -5.80%, P = 0.006) talar cartilage. Similarly, the CAI group had greater deformation relative to the control group for overall (-8.59% vs -3.46%, P = 0.038) and medial (-8.51% vs -3.31%, P = 0.043) talar cartilage after the dynamic loading condition. In the combined cohort, cartilage deformation was greater after static loading compared with dynamic in overall (-8.85% vs -6.03%, P = 0.003), medial (-9.38% vs -5.91%, P = 0.043), and lateral (-7.90% vs -5.65%, P = 0.009) cartilage. CONCLUSION: US is capable of detecting differences in cartilage deformation between those with CAI and uninjured controls after standardized physiologic loads. Across both groups, our results demonstrate that static loading results in greater cartilage deformation compared with dynamic loading.

Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents.

Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Rodents exposed to spaceflight or hind limb unloading (HLU) represent unique opportunities to evaluate this question. This study evaluated arthritic changes in the medial knee compartment that bears the highest loads across the knee after actual and simulated spaceflight, and recovery with subsequent full weight-bearing. Cartilage and meniscal degradation in mice were measured via microCT, histology, and proteomics and/or biochemically after: (1) ~ 35 days on the International Space Station (ISS); (2) 13-days aboard the Space Shuttle Atlantis; or (3) 30 days of HLU, followed by a 49-day weight-bearing readaptation with/without exercise. Cartilage degradation post-ISS and HLU occurred at similar spatial locations, the tibial-femoral cartilage-cartilage contact point, with meniscal volume decline. Cartilage and meniscal glycosaminoglycan content were decreased in unloaded mice, with elevated catabolic enzymes (e.g., matrix metalloproteinases), and elevated oxidative stress and catabolic molecular pathway responses in menisci. After the 13-day Shuttle flight, meniscal degradation was observed. During readaptation, recovery of cartilage volume and thickness occurred with exercise. Reduced weight-bearing from either spaceflight or HLU induced an arthritic phenotype in cartilage and menisci, and exercise promoted recovery.

Trends in Articular Cartilage Tissue Engineering: 3D Mesenchymal Stem Cell Sheets as Candidates for Engineered Hyaline-Like Cartilage.

Articular cartilage defects represent an inciting factor for future osteoarthritis (OA) and degenerative joint disease progression. Despite multiple clinically available therapies that succeed in providing short term pain reduction and restoration of limited mobility, current treatments do not reliably regenerate native hyaline cartilage or halt cartilage degeneration at these defect sites. Novel therapeutics aimed at addressing limitations of current clinical cartilage regeneration therapies increasingly focus on allogeneic cells, specifically mesenchymal stem cells (MSCs), as potent, banked, and available cell sources that express chondrogenic lineage commitment capabilities. Innovative tissue engineering approaches employing allogeneic MSCs aim to develop three-dimensional (3D), chondrogenically differentiated constructs for direct and immediate replacement of hyaline cartilage, improve local site tissue integration, and optimize treatment outcomes. Among emerging tissue engineering technologies, advancements in cell sheet tissue engineering offer promising capabilities for achieving both in vitro hyaline-like differentiation and effective transplantation, based on controlled 3D cellular interactions and retained cellular adhesion molecules. This review focuses on 3D MSC-based tissue engineering approaches for fabricating "ready-to-use" hyaline-like cartilage constructs for future rapid in vivo regenerative cartilage therapies. We highlight current approaches and future directions regarding development of MSC-derived cartilage therapies, emphasizing cell sheet tissue engineering, with specific focus on regulating 3D cellular interactions for controlled chondrogenic differentiation and post-differentiation transplantation capabilities.

From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside.

Osteoarthritis (OA) is currently the most widespread musculoskeletal condition and primarily affects weight-bearing joints such as the knees and hips. Importantly, knee OA remains a multifactorial whole-joint disease, the appearance and progression of which involves the alteration of articular cartilage as well as the synovium, subchondral bone, ligaments, and muscles through intricate pathomechanisms. Whereas it was initially depicted as a predominantly aging-related and mechanically driven condition given its clear association with old age, high body mass index (BMI), and joint malalignment, more recent research identified and described a plethora of further factors contributing to knee OA pathogenesis. However, the pathogenic intricacies between the molecular pathways involved in OA prompted the study of certain drugs for more than one therapeutic target (amelioration of cartilage and bone changes, and synovial inflammation). Most clinical studies regarding knee OA focus mainly on improvement in pain and joint function and thus do not provide sufficient evidence on the possible disease-modifying properties of the tested drugs. Currently, there is an unmet need for further research regarding OA pathogenesis as well as the introduction and exhaustive testing of potential disease-modifying pharmacotherapies in order to structure an effective treatment plan for these patients.

Articular chondroprogenitors in platelet rich plasma for treatment of osteoarthritis and osteochondral defects in a rabbit knee model.

BACKGROUND: Articular chondroprogenitors are a promising contender for cartilage repair due to their inherent nature which stands primed for chondrogenesis and minimal hypertrophic preponderance. Platelet rich plasma (PRP) has been extensively used for treating cartilage defects and osteoarthritis (OA), due to its chondro-inductive properties and abundant pool of growth factors. The aim of this study was to assess the efficacy of chondroprogenitors injected with PRP versus PRP alone in the healing of experimentally created early OA and osteochondral defects (OCD) in a rabbit model. METHODS: Adult New Zealand White male rabbits were used for cell and PRP isolation. Chondroprogenitors were isolated by fibronectin adhesion assay, labelled with iron oxide, characterized for surface markers, differential potential and expanded. PRP was isolated by double spin centrifugation using a TriCell kit. Study groups included (a) Monosodium iodoacetate induced early OA and (b) critical OCD. Following intervention (test arm: PRP+ chondroprogenitors and control arm: PRP), assessment was performed at 6- and 12-weeks which included histopathological examination and scoring (OARSI and Modified Wakitani score), immunohistochemistry analysis (Collagen type II and X) and synovial fluid S100A12 levels. RESULTS AND CONCLUSION: Comparable, evident healing was noticed in both test and control arms when the OA group samples were assessed at both time points. In the OCD group, PRP alone exhibited significantly better results than the test arm, although repair was notable in both interventions. Further evaluation of chondroprogenitors is required to assess their role as a standalone therapy and in combination with PRP to further cartilage regeneration.

Frequency of Growth Differentiation Factor 5 rs143383 and asporin D-repeat polymorphisms in patients with hand and knee osteoarthritis in Kurdistan province, Iran.

AIM: Osteoarthritis (OA) is the most common chronic joint disorder, resulting from the breakdown of joint cartilage. It occurs in the knees, hands, and hips, leading to pain, stiffness, inflammation, and swelling. METHODS: In this study, 100 hand and knee OA patients, meeting the American College of Rheumatology criteria were included in the case group, and 100 healthy individuals were allocated to the control group. Blood samples were collected from the participants. After DNA extraction, genotyping was carried out for GDF5 rs143383 C/T polymorphism by allele-specific polymerase chain reaction (ASPCR) and for D-repeat alleles of asporin (ASPN) by conventional PCR assay. RESULTS: The results showed that the frequency of the D14 allele of ASPN was significantly higher than other alleles in the case group (P = .0001). Also, the frequency of the D14 allele among women was significantly higher than in men (P = .004). Moreover, the frequency of the TT allele in GDF5 rs143383 C/T polymorphism was significantly higher than the CC and CT alleles in the case group, compared with the control group (P = .001). A significant difference was found between the TT allele and other alleles in female and male patients compared with the control group (P = .02). CONCLUSIONS: The D14 allele of the ASPN gene and TT allele of the GDF5 gene (rs143383 + 104T/C) are associated with hand and knee OA in the Kurdish population, indicating that these alleles could be risk factors for OA, at least in our populations.

An Update on the Role of Leptin in the Immuno-Metabolism of Cartilage.

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration.