Subchondral Bone Thickness Research Articles

Osteoarthritis early-, mid- and late-stage progression in the rat medial meniscus transection model.

Osteoarthritis is a degenerative disease of synovial joints affecting all tissues, including articular cartilage and subchondral bone. Osteoarthritis animal models can recapitulate aspects of human disease progression and are used to test efficacy of drugs, biomaterials, and cell therapies. The rat medial meniscus transection (MMT) model is a surgically induced posttraumatic osteoarthritis model commonly used for preclinical therapeutic screening. We describe herein, the qualitative and quantitative changes to articular cartilage, subchondral bone, and formation of osteophytes at early-, mid-, and late-stages of osteoarthritis progression. Tibia of MMT-operated animals showed proteoglycan loss and fibrillation along articular cartilage surfaces as early as 3-weeks post-surgery. With contrast-enhanced micro-CT technique, quantitative, 3-dimensional analysis of the tibia showed that the articular cartilage thickened at 3- and 6-weeks post-surgery and decreased at 12-weeks post-surgery. This decreased cartilage thickness corresponded with increased lesions in the articular cartilage that led to its full degradation and exposing the subchondral bone layer. Further, subchondral bone thickening was significant at 6-weeks post-surgery and followed cartilage damage. Osteophytes were found as early as 3-weeks post-surgery and coincided with articular cartilage degradation. Cartilaginous osteophytes preceded mineralization, suggesting endochondral ossification. The rat MMT model has predominantly been used out to 3-weeks, and most studies determined the effect of therapies to delay or prevent the onset of osteoarthritis. We provide evidence that an extension of the rat MMT model out to 6- and 12-weeks more resembled severe phenotypes of human osteoarthritis. Thus, evaluating novel therapeutics at late-stage will be important for eventual clinical translation.

Changes in the Articular Cartilage Thickness in Patients with Symptomatic Rotator Cuff Tears: A Prospective Study with a Mean 5-Year Follow-Up.

Objectives: The purpose of this study was to prospectively investigate the progression of cartilage thinning in patients with symptomatic rotator cuff tears using MRI. Methods: Two hundred twenty-five consecutive patients with symptomatic rotator cuff tears visited our institute between 2009 and 2019. Of these, 28 shoulders of 27 patients (mean age, 65 years) who underwent at least two magnetic resonance imaging (MRI) examinations were prospectively enrolled. They all received conservative treatment. The mean follow-up was 67 months. Changes in cartilage thickness and the combined cartilage and subchondral bone thickness at the initial and final MRI were measured using a RadiAnt DICOM-viewer (Medixant, Poznan, Poland). The cartilage thickness of the humeral head was measured in the oblique coronal and sagittal images. The glenoid cartilage was measured in the axial and oblique coronal images. Results: At an average period of 5 years, 12 of 28 shoulders (42%) showed more than a 30% decrease in cartilage thickness in the humeral head. The glenoid showed cartilage thinning in only one shoulder (4%). In the humeral head, progressive cartilage thinning was seen mainly in the anterior and posterior parts of the humeral head in the sagittal plane. In the glenoid, progressive cartilage thinning was seen on the entire surface except the posterior area. There was no significant difference in cartilage thickness between the first and final follow-ups for both the humeral head and the glenoid. Conclusions: A total of 12 of 28 shoulders (42%) showed more than a 30% decrease in cartilage thickness in the humeral head, which was mainly observed in the anterior and posterior areas of the humeral head.

The Hounsfield Unit Values of Talar Subchondral Bone Predict Articular Cartilage Degeneration in Patients With Ankle Osteoarthritis.

Therapeutic strategies for ankle osteoarthritis (OA) are determined based on OA staging, alignment, and articular cartilage conditions. However, it is difficult to evaluate the degeneration of the remaining cartilage using imaging modalities. Subchondral bone plays a crucial role in maintaining cartilage homeostasis. Measurement of local Hounsfield unit (HU) values allows for the quantitative assessment of small changes in the subchondral bone. This study aimed to evaluate a relationship between the HU values of the subchondral bone and the histologic findings of articular cartilage in ankle OA. The talar articular surface was harvested from 14 ankles during arthroplasty. The talus was divided into anterior, middle, and posterior parts, and histologic specimens were prepared. Safranin O staining was performed and histologic findings were evaluated using the modified Mankin score. The regions of interest (ROIs) were set in the medial, central, and lateral regions of the specimens and computed tomography (CT) images, and the relationship between the HU values and histologic findings was analyzed. As OA progressed, cartilage defects increased. In conjunction with cartilage degeneration, the subchondral bone plate thickened, and the HU values increased. The HU value significantly and positively correlated with the modified Mankin score (r = 0.756), subchondral bone thickness (r = 0.674, P < .01), and trabecular bone area (r = 0.637). The cutoff HU values were 594 (sensitivity, 0.813; specificity, 0.944) for 3 points and 727 (sensitivity, 0.929; specificity, 0.782) for 11 points on the modified Mankin score. Significant correlations between HU values and cartilage degeneration in ankle OA were noted. Measuring HU values on CT images can be useful for evaluating the joint surface condition, including histologic findings of the remaining cartilage.

Melatonin Delays Arthritis Inflammation and Reduces Cartilage Matrix Degradation through the SIRT1-Mediated NF-κB/Nrf2/TGF-β/BMPs Pathway.

Cartilage, a flexible and smooth connective tissue that envelops the surfaces of synovial joints, relies on chondrocytes for extracellular matrix (ECM) production and the maintenance of its structural and functional integrity. Melatonin (MT), renowned for its anti-inflammatory and antioxidant properties, holds the potential to modulate cartilage regeneration and degradation. Therefore, the present study was devoted to elucidating the mechanism of MT on chondrocytes. The in vivo experiment consisted of three groups: Sham (only the skin tissue was incised), Model (using the anterior cruciate ligament transection (ACLT) method), and MT (30 mg/kg), with sample extraction following 12 weeks of administration. Pathological alterations in articular cartilage, synovium, and subchondral bone were evaluated using Safranin O-fast green staining. Immunohistochemistry (ICH) analysis was employed to assess the expression of matrix degradation-related markers. The levels of serum cytokines were quantified via Enzyme-linked immunosorbent assay (ELISA) assays. In in vitro experiments, primary chondrocytes were divided into Control, Model, MT, negative control, and inhibitor groups. Western blotting (WB) and Quantitative RT-PCR (q-PCR) were used to detect Silent information regulator transcript-1 (SIRT1)/Nuclear factor kappa-B (NF-κB)/Nuclear factor erythroid-2-related factor 2 (Nrf2)/Transforming growth factor-beta (TGF-β)/Bone morphogenetic proteins (BMPs)-related indicators. Immunofluorescence (IF) analysis was employed to examine the status of type II collagen (COL2A1), SIRT1, phosphorylated NF-κB p65 (p-p65), and phosphorylated mothers against decapentaplegic homolog 2 (p-Smad2). In vivo results revealed that the MT group exhibited a relatively smooth cartilage surface, modest chondrocyte loss, mild synovial hyperplasia, and increased subchondral bone thickness. ICH results showed that MT downregulated the expression of components related to matrix degradation. ELISA results showed that MT reduced serum inflammatory cytokine levels. In vitro experiments confirmed that MT upregulated the expression of SIRT1/Nrf2/TGF-β/BMPs while inhibiting the NF-κB pathway and matrix degradation-related components. The introduction of the SIRT1 inhibitor Selisistat (EX527) reversed the effects of MT. Together, these findings suggest that MT has the potential to ameliorate inflammation, inhibit the release of matrix-degrading enzymes, and improve the cartilage condition. This study provides a new theoretical basis for understanding the role of MT in decelerating cartilage degradation and promoting chondrocyte repair in in vivo and in vitro cultured chondrocytes.

Arthroscopy With Adipose-Derived Stromal Vascular Fraction Using a Selective Tissue Engineering Photo-Stimulation Technique for the Treatment of Mild to Moderate Knee Osteoarthritis

Osteoarthritis (OA) is characterized by articular cartilage degeneration, synovial inflammation, and subchondral bone thickening, affecting the synovial joint as an organ and leading to pain and disability. Subcutaneous stromal vascular fraction is safe and relieves pain, improves function, and repairs cartilage defects in patients with knee OA. Our goal is to describe step-by-step the arthroscopic treatment of mild to moderate knee OA with photo-stimulated stromal vascular fraction harvested from the thigh using a selective tissue engineering photo-stimulation (“One S.T.E.P.”) technique.

Comprehensive in vitro and in vivo investigations of the therapeutic potential of Jeju lava seawater salt in osteoarthritis

Salts play a crucial role in maintaining human health by regulating fluid levels and supporting various physiological processes. However, conventional seawater-derived salts are associated with microplastic pollution and pose potential health risks. Jeju lava seawater (JLS), sourced exclusively from Jeju Island, has emerged as a unique alternative, free of microplastics and enriched with essential minerals such as magnesium, calcium, zinc, and iron. In this study, we investigated the effects of JLS on osteoarthritis (OA) pathogenesis, focusing on chondrocyte metabolism and OA development. We performed surgical destabilization of the medial meniscus to establish a murine model of OA. We examined the expression of catabolic and anabolic factors in JLS-treated chondrocytes. Our cell viability assay revealed that JLS treatment was not cytotoxic to chondrocytes at concentrations ≤ 0.5%. Additionally, JLS treatment resulted in a concentration-dependent increase in the expression of anabolic factors like aggrecan, SOX9, and COL2A1 while decreasing the expression of catabolic factors such as MMP3, MMP13, ADAMTS4, and ADAMTS5 in the chondrocytes stimulated with pro-inflammatory cytokines. Although not statistically significant compared to the control group, JLS intake slightly attenuated the OARSI score, osteophyte score, synovitis score, subchondral bone thickness, and osteophyte size in the mouse model of OA. Conclusively, these results suggest that JLS ameliorates OA by positively influencing chondrocyte metabolism, making it a promising therapeutic candidate for OA management.

SUBCHONDRAL MICROCHANNEL NETWORK CHANGES IN EARLY OSTEOARTHRITIS

Articular cartilage (AC) and subchondral bone (SB) are intimately intertwined, forming a complex unit called the AC-SB interface. Our recent studies have shown that cartilage and bone marrow are connected by a three-dimensional network of microchannels (i.e. cartilage-bone marrow microchannel connector; CMMC), which differ microarchitecturally in number, size and morphology depending on the maturation stage of the bone and the region of the joint. However, the pathological significance of CMMC is largely unknown. Here, we quantitatively assessed how CMMC microarchitecture relates to cartilage condition and regional differences in early idiopathic osteoarthritis (OA).Two groups of cadaveric female human femoral heads (intact cartilage vs early cartilage lesions) were identified and biopsy-based high-resolution micro-CT imaging was used. Subchondral bone (SB) thickness, CMMC number, maximum and minimum CMMC size, and CMMC morphology were quantified and compared between the two groups. The effect of joint region and cartilage condition on each dependent variable was examined.The number and morphology of CMMCs were influenced by the region of the joint, but not by the cartilage condition. On the other hand, the minimum and maximum CMMC size was modified by both joint location and cartilage condition. The smallest CMMCs were consistently found in the load bearing region (LBR) of the joint. Compared to healthy subjects, the size of the microchannels was increased in early OA, most notably in the non-load bearing region (NLBR) and the peripheral rim (PR) of the femoral head. In addition, subchondral bone thinning was observed in early OA as a localized event associated with areas of partial chondral defect.Our data suggest an enlargement of the SB microchannel network and a collective structural deterioration of the SB in early idiopathic OA.

Silencing of STUB1 relieves osteoarthritis via inducing NRF2-mediated M2 macrophage polarization

ObjectivesShifting macrophages towards an anti-inflammatory state is key in treating osteoarthritis (OA) by reducing inflammation and tissue damage. However, the underlying mechanisms guiding this shift remain largely undefined. STUB1, an E3 ubiquitin ligase, known for its regulatory role in macrophage polarization. This study aims to explore the function and underlying action mechanisms of STUB1 in OA. MethodsAn in vivo OA model was established in rats. Hematoxylin-Eosin and safranin O-fast green staining were performed to reveal the hispathological injuries in knee-joint tissues. Immunohistochemistry and flow cytometry were performed to detect the distribution of M1 and M2 macrophages. The inflammatory response (TNF-α and IL-6 levels) was evaluated by ELISA. In vitro, the interaction between STUB1 and NFR2 was determined by CO-IP and pull-down assays. After treated with LPS (an in vitro model of OA), the viability and apoptosis of chondrocytes were measured by CCK-8 and flow cytometry, respectively. ResultsSilencing STUB1 alleviated OA in rats, as indicated by reduced subchondral bone thickness, knee synovitis score, histopathological damages, and inflammatory response. STUB1 silencing also decreased M1 macrophages and increased M2 macrophages in both in vivo and in vitro settings. NRF2 was identified as a target of STUB1, with STUB1 mediating its ubiquitination. Silencing NRF2 reversed the effects of STUB1 silencing on inducing M2 macrophage polarization. Furthermore, silencing STUB1 upregulated NRF2 expression in LPS-treated chondrocytes, promoting cell viability and inhibiting apoptosis. ConclusionSilencing STUB1 induces M2 macrophage polarization by inhibiting NRF2 ubiquitination, thereby contributing to the mitigation of OA.

Intra-articular delivery of micronized dehydrated human amnion/chorion membrane reduces degenerative changes after onset of post-traumatic osteoarthritis.

Background: Micronized dehydrated human amnion/chorion membrane (mdHACM) has reduced short term post-traumatic osteoarthritis (PTOA) progression in rats when delivered 24h after medial meniscal transection (MMT) and is being investigated for clinical use as a disease modifying therapy. Much remains to be assessed, including its potential for longer-term therapeutic benefit and treatment effects after onset of joint degeneration. Objectives: Characterize longer-term effects of acute treatment with mdHACM and determine whether treatment administered to joints with established PTOA could slow or reverse degeneration. Hypotheses: Acute treatment effects will be sustained for 6weeks, and delivery of mdHACM after onset of joint degeneration will attenuate structural osteoarthritic changes. Methods: Rats underwent MMT or sham surgery (left leg). mdHACM was delivered intra-articularly 24h or 3weeks post-surgery (n = 5-7 per group). Six weeks post-surgery, animals were euthanized and left tibiae scanned using equilibrium partitioning of an ionic contrast agent microcomputed tomography (EPIC-µCT) to structurally quantify joint degeneration. Histology was performed to examine tibial plateau cartilage. Results: Quantitative 3D µCT showed that cartilage structural metrics (thickness, X-ray attenuation, surface roughness, exposed bone area) for delayed mdHACM treatment limbs were significantly improved over saline treatment and not significantly different from shams. Subchondral bone mineral density and thickness for the delayed treatment group were significantly improved over acute treated, and subchondral bone thickness was not significantly different from sham. Marginal osteophyte degenerative changes were decreased with delayed mdHACM treatment compared to saline. Acute treatment (24h post-surgery) did not reduce longer-term joint tissue degeneration compared to saline. Histology supported µCT findings and further revealed that while delayed treatment reduced cartilage damage, chondrocytes displayed qualitatively different morphologies and density compared to sham. Conclusion: This study provides insight into effects of intra-articular delivery timing relative to PTOA progression and the duration of therapeutic benefit of mdHACM. Results suggest that mdHACM injection into already osteoarthritic joints can improve joint health, but a single, acute mdHACM injection post-injury does not prevent long term osteoarthritis associated with meniscal instability. Further work is needed to fully characterize the durability of therapeutic benefit in stable osteoarthritic joints and the effects of repeated injections.

Clinical evaluation of the three-dimensional printed strut-type prosthesis combined with autograft reconstruction for giant cell tumor of the distal femur.

This study aimed to describe the design and surgical techniques of a three-dimensional (3D) printed strut-type prosthesis with a porous titanium surface for distal femur giant cell tumors of bone (GCTB) and evaluate the short-term clinical outcomes. From June 2018 to January 2021, 9 consecutive patients with grade I or II GCTB in the distal femur underwent extended intralesional curettage followed by 3D-printed strut-type prosthesis combined with autograft reconstruction were retrospectively reviewed to assess their clinical and radiographic outcomes. All patients were followed up for 30.8 ± 7.5 months (18-42 months) after surgery. The mean affected subchondral bone percentage and the mean subchondral bone thickness before surgery was 31.8% ± 9.6% (range, 18.2% ~50.2%) and 2.2 ± 0.8mm (range, 1.2-4.0mm), respectively. At the final follow-up, all the patients were alive without local recurrence; no postoperative complications were observed. Patients had significant improvements in postoperative MSTS-93 score [(26.7 ± 2.4) vs. (18.8 ± 3.7), P < 0.05], and ROM [(122.8° ± 9.1°) vs. (108.3° ± 6.1°), P < 0.05] compared with their preoperative statuses. Furthermore, the mean subchondral bone thickness has increased to 10.9 ± 1.3mm (range, 9.1-12.1mm). 3D-printed strut-type prosthesis combined with autograft reconstruction provides acceptable early functional and radiographic outcomes in patients with grade I or II GCTB in distal femur due to the advantages of the prosthesis such as good biocompatibility, osseointegration capacity, and subchondral bone protection. If our early outcomes can be further validated in studies with more patients and sufficient follow-up, this method may be evaluated as an alternative for the treatment of grade I or II GCTB in the distal femur.

CC-Chemokine Receptor-2 Expression in Osteoblasts Contributes to Cartilage and Bone Damage during Post-Traumatic Osteoarthritis.

In osteoarthritis (OA), bone changes are radiological hallmarks and are considered important for disease progression. The C-C chemokine receptor-2 (CCR2) has been shown to play an important role in bone physiology. In this study, we investigated whether Ccr2 osteoblast-specific inactivation at different times during post-traumatic OA (PTOA) progression improves joint structures, bone parameters, and pain. We used a tamoxifen-inducible Ccr2 inactivation in Collagen1α-expressing cells to obtain osteoblasts lacking Ccr2 (CCR2-Col1αKO). We stimulated PTOA changes in CCR2-Col1αKO and CCR2+/+ mice using the destabilization of the meniscus model (DMM), inducing recombination before or after DMM (early- vs. late-inactivation). Joint damage was evaluated at two, four, eight, and twelve weeks post-DMM using multiple scores: articular-cartilage structure (ACS), Safranin-O, histomorphometry, osteophyte size/maturity, subchondral bone thickness and synovial hyperplasia. Spontaneous and evoked pain were assessed for up to 20 weeks. We found that early osteoblast-Ccr2 inactivation delayed articular cartilage damage and matrix degeneration compared to CCR2+/+, as well as DMM-induced bone thickness. Osteophyte formation and maturation were only minimally affected. Late Collagen1α-Ccr2 deletion led to less evident improvements. Osteoblast-Ccr2 deletion also improved static measures of pain, while evoked pain did not change. Our study demonstrates that Ccr2 expression in osteoblasts contributes to PTOA disease progression and pain by affecting both cartilage and bone tissues.

CARTILAGE AND SUBCHONDRAL BONE CHANGES IN OSTEOARTHRITIS CAN BE DETECTED QUANTITATIVELY USING IN VIVO IMAGING

Cartilage diseases have a significant impact on the patient's quality of life and are a heavy burden for the healthcare system. Better understanding, early detection and proper follow-up could improve quality of life and reduce healthcare related costs. Therefore, the aim of this study was to evaluate if difference between osteoarthritic (OA) and non-osteoarthritic (non-OA) knees can be detected quantitatively on cartilage and subchondral bone levels with advanced but clinical available imaging techniques.Two OA (mean age = 88.3 years) and three non-OA (mean age = 51.0 years) human cadaveric knees were scanned two times. A high-resolution peripheral quantitative computed tomography (HR-pQCT) scan (XtremeCT, Scanco Medical AG, Switzerland) was performed to quantify the bone microstructure. A contrast-enhanced clinical CT scan (GE Revolution Evo, GE Medical Systems AG, Switzerland) was acquired with the contrast agent Visipaque 320 (60 ml) to measure cartilage. Subregions dividing the condyle in four parts were identified semi-automatically and the images were segmented using adaptive thresholding. Microstructural parameters of subchondral bone and cartilage thickness were quantified.The overall cartilage thickness was reduced by 0.27 mm between the OA and non-OA knees and the subchondral bone quality decreased accordingly (reduction of 33.52 % in BV/TV in the layer from 3 to 8 mm below the cartilage) for the femoral medial condyle. The largest differences were observed at the medial part of the femoral medial condyle both for cartilage and for bone parameters, corresponding to clinical observations.Subchondral bone microstructural parameters and cartilage thickness were quantified using in vivo available imaging and apparent differences between the OA and non-OA knees were detected. Those results may improve OA follow-up and diagnosis and could lead to a better understanding of OA. However, further in vivo studies are needed to validate these methods in clinical practice.

Treadmill Exercise Suppresses Histological Progression of Disuse Atrophy in Articular Cartilage in Rat Knee Joints during Hindlimb Suspension.

The purpose of this study was to determine the preventive effects of treadmill exercise or physiological loading on disuse atrophy in the rat knee joint cartilage and bone during hindlimb suspension. Twenty male rats were divided into 4 experimental groups, including the control, hindlimb suspension, physiological loading, and treadmill walking groups. Histological changes in the articular cartilage and bone of the tibia were histomorphometrically and immunohistochemically evaluated 4 weeks after the intervention. Compared with the control group, the hindlimb suspension group showed thinning of cartilage thickness, decreased matrix staining, and decreased proportion of noncalcified layers. Cartilage thinning, decreased matrix staining, and decreased noncalcified layers were suppressed in the treadmill walking group. The physiological loading group exhibited no significant suppression of cartilage thinning or decreased noncalcified layers, but the decreased matrix staining was significantly suppressed. No significant prevention of bone mass loss or changes in subchondral bone thickness were detected after physiological loading or treadmill walking. Disuse atrophy of the articular cartilage caused by unloading conditions could be prevented by treadmill walking in rat knee joints.

THE RELATIONSHIP BETWEEN KNEE JOINT ALIGNMENT, 3-D JOINT SPACE WIDTH AND SUBCHONDRAL BONE PARAMETERS IN INVIDUALS WITH RADIOGRAPHIC OSTEOARTHRITIS: A MOST INVESTIGATION

Joint alignment is an important factor in OA affecting how forces pass through the knee. The increasing use of weight bearing computed tomography (WBCT) in OA research has made the weight bearing stance an important consideration in 3-D imaging analysis, but its influence through biomechanics on the joint and subchondral bone is not fully understood. To investigate the relationship between knee joint alignment and 3-D joint parameters derived from joint space mapping of WBCT imaging in individuals with radiographic OA. WBCT of both knees was acquired at the 144-month visit of the Multicenter Osteoarthritis Study (MOST). Knees with a KLG ≥2 were included in the analysis, taking the side with higher KLG or averaging subsequent results from both sides if equal. Joint space mapping was performed to obtain the 3-D JSW distribution along with femoral (f) and tibial (t) subchondral bone thickness (ST) and trabecular attenuation (TA). Everyone's knee parameter maps were then transferred to a canonical joint surface. Alignment of the knee joint was measured as the angle between the central axis of the distal femur and proximal tibia in a coronal multiplanar reformat slab of the WBCT data: neutral alignment was set as zero with varus signed positive (figure part (a)). Statistical parametric mapping (SPM) was performed using a general linear model to test the dependence of each 3-D parameter distribution on alignment controlling for age, sex, mass, height, and joint space shape modes. SPM results were plotted on the canonical joint surface with unmasked regions representing a significance level of P<0.05. 136 knees were included in the analysis, 84 of which were females. Mean ± SD age was 66.4 ± 9.8 yrs; mass 85.3 ± 17.8 kg; height 1.69 ± 0.1 m. The distribution of radiographic grading was KL2 = 103; KL3 = 32; KL4 = 1. Mean alignment was 0.38 ± 3.80°. For each degree from valgus to varus, JSW was significantly narrower in the medial compartment and wider in the lateral compartment by up to 0.1 mm (figure part (d)). While TA was significantly greater by up to 10 AU in the medial femur (figure part (b)) and medial tibia (figure part (f)), there was up to 0.05 mm significantly thinner ST in the lateral femur (figure part (c)) and lateral tibia (figure part (e)). The opposite effects can be inferred for each degree towards valgus. The same analysis on KLG 0 and 1 knees in the same cohort (mean ± SD alignment 0.66 ± 2.94°) revealed no significant relationships. Subchondral bone plate and trabecular bone appear to behave differently in the medial and lateral compartments when considering knee joint alignment in individuals with OA. Greater subchondral trabecular bone attenuation was seen in the medial compartment with varus alignment, while greater subchondral bone plate thickness was seen in the lateral compartment with valgus alignment. Whether alignment is the cause or effect of OA and any altered biomechanics that may influence bone and joint space behaviour requires further investigation, but this study does establish that the forces associated with alignment appear to have different effects on subchondral bone in different compartments. National Institutes of Health, University of Kansas (R01AR071648), University of Iowa (U01AG18832) and University of California-San Francisco (U01AG19069). NS is a consultant for Integra BioLife, Trice Medical and Pacira Biosciences. TT has been a consultant for Curvebeam AI. The authors would like to thank participants and staff of the MOST study. CORRESPONDENCE ADDRESS: [email protected]

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.

Does the tidemark location matter in osteochondral allograft transplantation? A finite element analysis

<h2>ABSTRACT</h2><h3>OBECTIVE</h3> The purpose of this study is to evaluate the impact that osteochondral allograft cartilage thickness has on contact pressures, and to simulate whether a mismatch of the subchondral bony interface relative to the host-recipient site results in altered biomechanics. <h3>METHODS</h3> Properties of articular cartilage and bone were incorporated into a finite element model to create a simulated osteochondral lesion (diameter: 10mm, height: 10mm, cartilage thickness: 2mm, subchondral bone thickness: 8mm). Five osteochondral plugs were constructed to fill the defect, with cartilage-to-bone ratios between 1:9 and 1:1. The plugs were inserted and given a static downward force of 5000N. Resultant stresses and displacements were measured. <h3>RESULTS</h3> The 2:8 cartilage-to-bone ratio plug, matched with the recipient site, was deemed optimal based on its resultant stress and displacement. The 1:9 plug displaced less than the 2:8 match and endured greater stress per unit of cartilage volume, whereas the 3:7 plug also displayed similar displacement to the 1:9 plug but had greater cartilage volume and was able to distribute less stress per unit of cartilage volume. The 4:6 plug displaced to a similar extent as the 3:7 plug but displayed a unique pattern of strain. The 5:5 plug was considered non-functional, as the majority of displacement was seen in the cartilage of the recipient site rather than in the plug itself. <h3>CONCLUSION</h3> The relationship between the cartilage-to-bone ratio in osteochondral allografts and that of their surroundings significantly impacts the distribution of stresses and predilection for micro-motion at the repair site.

Early patellofemoral cartilage and bone pathology in a rat model of noninvasive anterior cruciate ligament rupture

ABSTRACT Objective Anterior cruciate ligament rupture (ACLR) is a risk factor for the development of post-traumatic osteoarthritis (PTOA). While PTOA in the tibiofemoral joint compartment is well-characterized, very little is known about pathology in the patellofemoral compartment after ACL injury. Here, we evaluated the extent to which ACLR induces early patellofemoral joint damage in a rat model. Methods Adult female Lewis rats were randomized to noninvasive ACLR or Sham. Two weeks post-injury, contrast-enhanced micro-computed tomography (µCT) of femoral and patellar cartilage was performed using 20% v/v ioxaglate. Morphometric parameters of femoral trochlear and patellar cartilage, subchondral bone, and trabecular bone were derived from µCT. Sagittal Safranin-O/Fast-Green-stained histologic sections were graded using the OARSI score in a blinded fashion. Results Cartilage and bone remodelling consistent with an early PTOA phenotype were observed in both femoral trochleas and patellae. ACLR caused osteophyte formation of the patella and pathology in the superficial zone of articular cartilage, including surface fibrillation, fissures, increased cellularity, and abnormal chondrocyte clustering. There were significant increases in thickness of patellar and trochlear cartilage. Loss of subchondral bone thickness, bone volume fraction, and tissue mineral density, as well as changes to patellar and trochlear trabecular microarchitecture, were indicative of catabolic bone remodelling. Several injury-induced changes, including increased cartilage thickness and trabecular spacing and decreased trabecular number were more severe in the patella compared to the trochlea. Conclusion The patellofemoral joint develops mild but evident pathology in the early period following ACL rupture, extending the utility of this model to the study of patellofemoral PTOA.

Changes of the subchondral bone microchannel network in early osteoarthritis

We have identified a 3D network of subchondral microchannels that connects the deep zone of cartilage to the bone marrow (i.e., cartilage-bone marrow microchannel connectors; CMMC). However, the pathological significance of CMMC is largely unknown. Here, we quantitatively evaluated how the CMMC microarchitecture is related to cartilage condition, as well as regional differences in early idiopathic osteoarthritis (OA). Two groups of cadaveric female human femoral heads (intact cartilage vs early cartilage lesions) were identified, and a biopsy-based high-resolution micro-CT imaging was employed. Subchondral bone (SB) thickness, CMMC number, maximum and minimum CMMC size, and the CMMC morphology were quantified and compared between the two groups. The effect of joint's region and cartilage condition was examined on each dependent variable. The CMMC number and morphology were affected by region of the joint, but not by cartilage condition. On the other hand, the minimum and maximum CMMC size was changed by both the location on the joint, as well as the cartilage condition. The smallest CMMC were consistently detected at the load-bearing region (LBR) of the joint. Compared to non-pathological subjects, the size of the microchannels was enlarged in early OA, most noticeably at the non-load-bearing region (NLBR) and the peripheral rim (PR) of the femoral head. Furthermore, subchondral bone thinning was observed in early OA as a localized occurrence linked with areas of partial chondral defect. Our data point to an enlargement of the SB microchannel network, and a collective structural deterioration of SB in early idiopathic OA.

Effects of in vivo fatigue-induced microdamage on local subchondral bone strains

Biomechanical strain is a major stimulus of subchondral bone (SCB) tissue adaptation in joints but may also lead to initiation and propagation of microcracks, highlighting the importance of quantifying the intratissue strain in subchondral bone. In the present study, we used micro computed tomography (μCT) imaging, mechanical testing, and digital image correlation (DIC) techniques to evaluate the biomechanical strains in equine SCB under impact compression applied through the articular surface. We aimed to investigate the effects of in vivo accumulated microdamage in equine SCB on the distribution of mechanical impact strain through the articular cartilage. Under the applied strain of 2.0 ± 0.1% (mean ± standard deviation, n=15) to the articular surface of cartilage-bone plugs, the overall thickness of the SCB developed eSCBOverall = 0.7 ± 0.2% in all specimens. Contours of high strains in specimens without microdamage (NDmg) aligned parallel to the cartilage-bone interface with peak tensile, ϵt, and compressive, ϵc, strains of 0.5 ± 0.3% and 1.2 ± 0.4%, respectively at the time of peak compression (n=7). In damaged specimens (Dmg), contours of high strains aligned with the cracks in the imaged plane with peak strains of ϵt= 1.2 ± 0.8% and ϵc= 3.5 ± 2.2%, respectively (n=7). Microdamage was the main predictor of the normalised compressive and tensile strains across the SCB thickness. Results of multivariable analyses revealed presence of microdamage, distance from the articular surface and TMD were the main predictors of normalised compressive and tensile strain. Strain was greater in the superficial bone, particularly for specimens with microdamage. In vivo fatigue-induced microdamage is an important predictor of local subchondral bone strains.

Transient spontaneous osteonecrosis of the knee (SONK) shortly after SARS-CoV-2 infection: A report of 2 cases

This article describes 2 cases of post-coronavirus disease 2019 (COVID-19) transient spontaneous osteonecrosis of the knee (PCT-SONK) observed in patients who had previously recovered from COVID-19 without corticosteroid administration. The possible pathomechanisms by which a recent SARS-CoV-2 infection may contribute as a causative factor for osteonecrosis are reviewed, and the differential diagnosis and treatment are discussed. Two patients (males, 45- and 47-year-old) presented with sudden onset knee pain with no trauma history. The pain persisted during rest and at night. On magnetic resonance imaging (MRI), no subchondral bone thickening was observed; bone edema was diffusely distributed in the whole femoral condyle, in contrast to the more focal edema that is typically concentrated mainly around the subchondral region in classic SONK. Both patients were treated nonoperatively with no weight bearing and pharmacological agents, and complete resolution of symptoms was achieved. A follow-up MRI 10 weeks after presentation revealed a near-complete loss of signal in the medial femoral condyle in both patients. Orthopedic surgeons should be cautious when sudden knee pain without concurrent trauma or a history of injury occurs shortly after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, even with mild COVID-19 illness. While some studies report the development of post-COVID-19 osteonecrosis after lower doses of corticosteroids and sooner after their administration than in comparable non-COVID-19 cases, our study is the first to report 2 cases with no corticosteroid administration at all. Therefore, the authors believe it adds to the body of knowledge on the potential connections between COVID-19 and PCT-SONK. The transient nature of symptoms and radiological findings suggest that aggressive surgical treatment of non-injury local bone edema occurring shortly after SARS-CoV-2 infection should be avoided.