Subchondral Bone Alterations Research Articles

NADPH OXIDASE 4 DEFICIENCY ATTENUATES EXPERIMENTAL OSTEOARTHRITIS IN MICE

Purpose: Osteoarthritis (OA) is a degenerative disease characterized by damage of articular cartilage, alteration of subchondral bone, and inflamed synovium. Articular cartilage is essentially composed of an avascular matrix produced by chondrocytes. In OA, articular cartilage follows a progressive degeneration, where low-grade inflammation plays a pivotal role through an oxidative stress-dependent mechanism and exposure to reactive oxygen species (ROS). In chondrocytes, the only cells of the cartilage, NADPH oxidase 4 (NOX4) is one of the major ROS producers and plays a major role in catabolism regulation.

Systemic inhibition or global deletion of CaMKK2 protects against post-traumatic osteoarthritis

To investigate the role of Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) in post-traumatic osteoarthritis (PTOA). Destabilization of the medial meniscus (DMM) or sham surgeries were performed on 10-week-old male wild-type (WT) and Camkk2-/- mice. Half of the DMM-WT mice and all other cohorts (n=6/group) received tri-weekly intraperitoneal (i.p.) injections of saline whereas the remaining DMM-WT mice (n=6/group) received i.p. injections of the CaMKK2 inhibitor STO-609 (0.033mg/kg body weight) thrice a week. Study was terminated at 8- or 12-weeks post-surgery, and knee joints processed for microcomputed tomography imaging followed by histology and immunohistochemistry. Primary articular chondrocytes were isolated from knee joints of 4-6-day-old WT and Camkk2-/- mice, and treated with 10ng/ml interleukin-1β (IL)-1β for 24 or 48h to investigate gene and protein expression. CaMKK2 levels and activity became elevated in articular chondrocytes following IL-1β treatment or DMM surgery. Inhibition or absence of CaMKK2 protected against DMM-associated destruction of the cartilage, subchondral bone alterations and synovial inflammation. When challenged with IL-1β, chondrocytes lacking CaMKK2 displayed attenuated inflammation, cartilage catabolism, and resistance to suppression of matrix synthesis. IL-1β-treated CaMKK2-null chondrocytes displayed decreased IL-6 production, activation of signal transducer and activator of transcription 3 (Stat3) and matrix metalloproteinase 13 (MMP13), indicating a potential mechanism for the regulation of inflammatory responses in chondrocytes by CaMKK2. Our findings reveal a novel function for CaMKK2 in chondrocytes and highlight the potential for its inhibition as an innovative therapeutic strategy in the prevention of PTOA.

Role of peroxiredoxin 6 in the chondroprotective effects of microvesicles from human adipose tissue-derived mesenchymal stem cells.

BackgroundOsteoarthritis (OA) is a joint disease characterized by cartilage degradation, low-grade synovitis and subchondral bone alterations. In the damaged joint, there is a progressive increase of oxidative stress leading to disruption of chondrocyte homeostasis. The modulation of oxidative stress could control the expression of inflammatory and catabolic mediators involved in OA. We have previously demonstrated that extracellular vesicles (EVs) present in the secretome of human mesenchymal stem cells from adipose tissue (AD-MSCs) exert anti-inflammatory and anti-catabolic effects in OA chondrocytes. In the current work, we have investigated whether AD-MSC EVs could regulate oxidative stress in OA chondrocytes as well as the possible contribution of peroxiredoxin 6 (Prdx6).MethodsMicrovesicles (MV) and exosomes (EX) were isolated from AD-MSC conditioned medium by differential centrifugation with size filtration. The size and concentration of EVs were determined by resistive pulse sensing. OA chondrocytes were isolated from knee articular cartilage of advanced OA patients. 4-Hydroxynonenal adducts, IL-6 and MMP-13 were determined by enzyme-linked immunosorbent assay. Expression of Prdx6 and autophagic markers was assessed by immunofluorescence and Western blotting. Prdx6 was downregulated in AD-MSCs by transfection with a specific siRNA.ResultsMV and to a lesser extent EX significantly reduced the production of oxidative stress in OA chondrocytes stimulated with IL-1β. Treatment with MV resulted in a dramatic upregulation of Prdx6. MV also enhanced the expression of autophagy marker LC3B. We downregulated Prdx6 in AD-MSCs by using a specific siRNA and then MV were isolated. These Prdx6-silenced MV failed to modify oxidative stress and the expression of autophagy markers. We also assessed the possible contribution of Prdx6 to the effects of MV on IL-6 and MMP-13 production. The reduction in the levels of both mediators induced by MV was partly reverted after Prdx6 silencing.ConclusionOur results indicate that EVs from AD-MSCs regulate the production of oxidative stress in OA chondrocytes during inflammation. Prdx6 may mediate the antioxidant and protective effects of MV.The translational potential of this article: This study gives insight into the protective properties of EVs from AD-MSCs in OA chondrocytes. Our findings support the development of novel therapies based on EVs to prevent or treat cartilage degradation.

Subchondral and intra-articular injections of bone marrow concentrate are a safe and effective treatment for knee osteoarthritis: a prospective, multi-center pilot study.

Subchondral bone is becoming a treatment target for knee OA patients, with promising early findings on the use of bone marrow aspirate concentrate (BMAC). The aim of this prospective, multi-centric pilot study was to evaluate safety as well as clinical and MRI outcomes of a combined approach of intra-articular and subchondral BMAC injections. Thirty patients (19 men, 11 women, 56.4 ± 8.1years) with symptomatic knee OA were treated with a combination of an intra-articular and two subchondral BMAC injections (femoral condyle and tibial plateau). Patients were evaluated at baseline and at 1-3-6-12months of follow-up with the IKDC subjective, VAS, KOOS, and EQ-VAS scores. The MRI evaluation was performed with the WORMS score. No major complications were reported and only two patients were considered treatment failures, requiring a new injective or surgical treatment. The IKDC subjective score improved significantly from 40.5 ± 12.5 to 59.9 ± 16.1 at 3months, 59.1 ± 12.2 at 6months, and 62.6 ± 19.4 at 12months (p < 0.0005). A similar improvement was reported for VAS pain and all KOOS subscales at all follow-ups, while EQ-VAS did not show any significant improvement. The MRI analysis showed a significant bone marrow edema reduction (p = 0.003), while the remaining WORMS parameters did not show any significant changes. The pilot evaluation of this combined BMAC injective treatment showed safety and positive outcome up to 12months of follow-up in patients with symptomatic knee OA associated with subchondral bone alterations. These findings suggest that targeting both subchondral bone and joint environment can provide promising results, and that BMAC can be a valid option for this combined approach to treatknee OA.

Extracorporeal shockwave treatment in knee osteoarthritis: therapeutic effects and possible mechanism.

Osteoarthritis (OA), the most common degenerative joint disease, is characterized by the cardinal symptoms of chronic pain and restricted joint activity. The complicated pathological changes associated with OA and unclear mechanistic etiology have rendered existing non-surgical OA management options unsatisfactory. Increasing clinical and experimental evidence suggests that extracorporeal shockwave therapy (ESWT) is beneficial in OA treatment. ESWT is found to have modifying effects on cartilage and subchondral bone alterations in OA progression, as well as the clinical complaints of patients, including chronic pain and limited joint activities. However, the specific treatment strategy regarding the dosage and frequency of ESWT is still underdetermined. This review discusses the existing evidence regarding the therapeutic indications and possible mechanism of ESWT for OA treatment.

Degradation of subchondral bone collagen in the weight-bearing area of femoral head is associated with osteoarthritis and osteonecrosis

BackgroundThe aim of the study was to evaluate the change of subchondral bone collagen and trabecular bone in the weight-bearing area of femoral head from patients with osteoarthritis (OA) or osteonecrosis of femoral head (ONFH), and discuss the effect of collagen degradation on OA and ONFH.MethodsFemoral heads from patients with femoral neck fracture (FNF) were collected as control group. All collected samples were divided into OA group (N = 10), ONFH group (N = 10), and FNF group (N = 10). Differences of subchondral bone collagen were compared through scanning electron microscope (SEM) observation, immunohistochemistry staining, and Masson’s trichrome staining. Alteration of subchondral bone was displayed through hematoxylin and eosin (H&E) staining and gross morphology.ResultsSEM results showed that collagen fibers in OA and ONFH group appeared to be thinner, rougher, sparser, and more wizened. Immunohistochemistry and Masson’s trichrome staining results demonstrated that the content of collagen fibers in the OA and ONFH group was obviously less than the FNF group. H&E staining results showed that trabecular bone in OA and ONFH group appeared to be thinner and ruptured. Gross morphology results showed that the degeneration and destruction of cartilage and subchondral bone in OA and ONFH group were severer than FNF group. The characteristics mentioned above in ONFH group were more apparent than OA group.ConclusionsThis study revealed that degradation of collagen fibers from subchondral bone in the weight-bearing area of femoral head was associated with OA and ONFH, which may help to find new therapeutic strategies of the diseases.

Percutaneous Skeletal Fixation of Painful Subchondral Bone Marrow Edema Utilizing an Injectable, Synthetic, Biocompatible Hyaluronic Acid–Based Bone Graft Substitute

Subchondral bone marrow edema (SBME) represents a pathologic alteration of subchondral bone. A strong correlation exists between its presence and the progression of osteoarthritis. Very few treatment options exist between the spectrum of conservative management and the definitive treatment of total knee arthroplasty (TKA). Tactoset® is an injectable synthetic, biocompatible hyaluronic acid–based bone graft substitute that allows for a minimally invasive treatment for painful SBME via percutaneous skeletal fixation (PSF). We present the technique of PSF using Tactoset.

Chondral Defects Cause Kissing Lesions in a Porcine Model.

To assess the development of kissing lesions 12 months after the generation of full-thickness chondral defects. Eight minipigs were randomized into 2 groups: the Φ8.5 mm full-thickness chondral defect group (8.5FT group) and the Φ6.5 mm full-thickness chondral defect group (6.5FT group). The Φ8.5 mm or Φ6.5 mm full-thickness chondral defects were prepared in the medial femoral condyle. Knee magnetic resonance imaging (MRI) was performed before sacrifice. India ink staining was performed to macroscopically assess kissing lesions. Histologic staining (hematoxylin-eosin [HE], safranin O/fast green, toluidine blue staining) and immunohistochemistry (collagen I, collagen II, collagen X, MMP-3) were performed. Microcomputed tomography analysis was completed to assess subchondral bone alterations. Obvious kissing lesions were observed on the tibial plateau. Knee MRI demonstrated high cartilage signal intensity in the medial femoral condyle and opposite tibial plateau. HE staining demonstrated cartilage fibrillation and prominent cell death. The depletion of safranin O, toluidine blue staining, and collagen II was observed in the kissing lesion areas. The kissing lesion areas demonstrated increased collagen I, Collagen X, and MMP-3 expression. The 8.5FT group showed a significantly lower mean trabecular number (2.80 1/mm) than the control group (3.26 1/mm). The 6.5FT group showed a significantly increased mean trabecular thickness (0.54 mm) and a decreased mean trabecular number (2.71 1/mm) compared to the control group (0.32 mm; 3.26 1/mm). Obvious kissing lesions were observed on the tibial plateau. Knee MRI demonstrated high cartilage signal The presented findings support the development of kissing lesions caused by full-thickness chondral defects.

Intraosseous injections of platelet rich plasma for knee bone marrow lesions treatment: one year follow-up.

Cartilage lesions are usually accompanied by subchondral bone alterations or bone marrow lesions (BMLs). BML associated with joint degeneration and cartilage lesions are considered to be predictors of rapidly progressing OA. Currently no existing treatment can fully halt OA progression. One of the approaches is an autologous, biological treatment based on the use of platelet rich plasma (PRP) injections. The purpose of this study is to assess the short-term effectiveness of intraosseous PRP injections, within the BML of individuals affected by OA, in ameliorating pain and improving knee functionality. The study involved 17 patients with an average age of 41.7 ± 14.3years old. OA stage was determined using the Kellgren-Lawrence grading system by performing radiographic scanning of the knee joint before surgical intervention. Patients with K-L grade 3 knee joint OA prevailed. Patient OA history varied between one and nineyears (average 5.2 ± 4.5years). Clinical and functional state of the knee were assessed by pain visual analogue scale (VAS) score, the Western Ontario and McMaster Universities Score (WOMAC), and the Knee Injury and Osteoarthritis Outcome Score (KOOS) which were filled out by patients previous to the surgical procedure at one, three, six and 12months post-operatively. Before surgery, in addition to standard blood tests, serum cartilage oligomeric matrix protein (COMP) levels were tested for all patients. Evaluation of preliminary results revealed a statistically significant reduction of pain based on the VAS score. A significant improvement was also observed in the patients' WOMAC score and in the overall KOOS score. Serum marker levels were initially elevated in our experimental patient group compared to the same marker in healthy control respondents, and continued to rise one month and three months following surgery, at six and 12month the level was similar as at three months. In our opinion, first COMP increasing can be caused by injection of platelet rich plasma. It is not adequate to interpret this growth in COMP levels as increased osteochondral degeneration. One year follow-up period showed good quality of life improvement, significant pain reduction, and essential MRI changes. The long-term observation of these cohort of patients combined with an analysis of MRI images is still ongoing.

LATERAL FEMORAL CONDYLE OSTEOCHONDRITIS DISSECANS: DOES WEIGHTBEARING ZONE LOCATION PREDICT HEALING?

Background: Osteochondritis dissecans (OCD) is a focal, idiopathic alteration of subchondral bone with potential for instability and disruption of adjacent articular cartilage that may result in premature (early secondary) osteoarthritis. Purpose: The purpose of this study was to evaluate differences in clinical, radiographic, and treatment outcomes in weightbearing (WB) versus non-weightbearing (NWB) lateral femoral condyle (LFC) OCDs. Methods: An IRB-approved retrospective review of 62 patients with LFC OCD lesions, 26 of which were weightbearing and 36 non-weightbearing (defined as Cahill and Berg sagittal zones B and C, respectively), treated at a single institution between 2004 and 2019 was performed. All participants were 18 years of age or younger at the time of diagnosis. Demographic and clinical characteristics, radiographic features, treatment modalities, and outcomes were evaluated. Continuous variables were analyzed using a Mann-Whitney test and a Kruskal-Wallis test when comparing across various groups. A Chi-square test was used to compare categorical variables. Results: The study cohort consisted of 40 (64.5%) male and 22 (35.5%) female participants, with an average age at diagnosis of 12.86 ± 2.74 years, and an average follow-up of 24 months. WB and NWB LFC OCDs had no differences in symptom chronicity or the presence of mechanical symptoms. NWB lesions were more likely to present with distinct ossification of the progeny bone segment (70.0% vs. 25.0%; p = 0.044) and were deeper lesions (MRI sagittal depth 7.11 vs. 5.96; p = 0.046). Across a variety of treatment modalities, NWB lesions were significantly more likely than WB lesions to demonstrate full radiographic healing at final follow-up (52.8% vs. 24.0%; p = 0.033). There was no difference in the likelihood of initial non-operative versus operative treatment selection or in the outcomes of non-operative treatment between the two lesion types. Additionally, OCDs in either zone were equally likely to be pain-free at final follow-up. Conclusion: Lateral femoral condylar OCD lesions in weightbearing and non-weightbearing zones have similar clinical presentation. However, lesions in non-weightbearing zones demonstrate improved radiographic healing at final follow-up. These data may aid in clinical decision-making and counseling during treatment of children and adolescents presenting with lateral femoral condylar OCD. [Figure: see text]

Subchondral bone deterioration in femoral heads in patients with osteoarthritis secondary to hip dysplasia: A case-control study.

ObjectivesResidual hip dysplasia is the most common underlying condition leading to secondary osteoarthritis (OA) of the hip. Subchondral bone alterations in OA secondary to hip dysplasia (HD-OA) are poorly investigated. The aim of the present study was to analyse the microarchitecture, bone remodelling and pathological alterations of subchondral bone in femoral heads from patients with HD-OA.MethodsSubchondral bone specimens were extracted from both weight-bearing and non–weight-bearing regions of femoral heads from 20 patients with HD-OA and 20 patients with osteoporotic femoral neck fracture, during hip replacement surgery. Micro-CT and histological examination were performed to assess the microarchitecture and histopathological changes.ResultsThe weight-bearing subchondral bone showed significantly more sclerotic microarchitecture and higher bone remodelling level in HD-OA as compared with osteoporosis. In the non–weight-bearing region, the two diseases shared similar microarchitectural characteristics, but higher bone remodelling level was detected in HD-OA. Distinct regional differences were observed in HD-OA, whereas the two regions exhibited similar characteristics in osteoporosis. In addition, HD-OA displayed more serious pathological alterations, including subchondral bone cyst, metaplastic cartilaginous tissue, bone marrow oedema and fibrous tissue, especially in the weight-bearing region.ConclusionsOsteoarthritic deteriorations of subchondral bone induced by hip dysplasia spread throughout the whole joint, but exhibit region-dependent variations, with the weight-bearing region more seriously affected. Biomechanical stress might exert a pivotal impact on subchondral bone homeostasis in hip dysplasia.The translational potential of this articleThe histomorphometric findings in the project indicate an early intervention for the development of hip dysplasia in clinic.

Early Alterations of Subchondral Bone in the Rat Anterior Cruciate Ligament Transection Model of Osteoarthritis.

Advances in research have shown that the subchondral bone plays an important role in the propagation of cartilage loss and progression of osteoarthritis (OA), but whether the subchondral bone changes precede or lead to articular cartilage loss remains debatable. In order to elucidate the subchondral bone and cartilage changes that occur in early OA, an experiment using anterior cruciate ligament transection (ACLT) induced posttraumatic OA model of the rat knee was conducted. Forty-two Sprague Dawley rats were divided into 2 groups: the ACLT group and the nonoperated control group. Surgery was conducted on the ACLT group, and subsequently rats from both groups were sacrificed at 1, 2, and 3 weeks postsurgery. Subchondral bone was evaluated using a high-resolution peripheral quantitative computed tomography scanner, while cartilage was histologically evaluated and scored. A significant reduction in the subchondral trabecular bone thickness and spacing was found as early as 1 week postsurgery in ACLT rats compared with the nonoperated control. This was subsequently followed by a reduction in bone mineral density and bone fractional volume at week 2, and finally a decrease in the trabecular number at week 3. These changes occurred together with cartilage degeneration as reflected by an increasing Mankin score over all 3 weeks. Significant changes in subchondral bone occur very early in OA concurrent with surface articular cartilage degenerative change suggest that factors affecting bone remodeling and resorption together with cartilage matrix degradation occur very early in the disease.

Local administration of halofuginone via osmotic infusion pumps inhibits transforming growth fac-tor-β signaling in subchondral bone

Objective To explore the impact of inhibition of transforming growth factor-β(TGF-β) signaling by local administration of halofuginone (HF) via osmotic infusion pumps on osteoarthritis (OA) pathogenesis and its underlying mechanism. Methods Knee OA models were induced by the anterior cruciate ligament transection (ACLT) in 30 3-month-old male SD rats. They were randomized by random number table into 3 equal groups (n=10): Sham, Vehicle+ACLT and HF+ACLT ones. Specific admin-istration of drugs was achieved via osmotic infusion pumps directly implanted in subchondral bone. Safranin O and fast green, H&E, immunofluorescence staining, CT-based microangiography and bone micro-CT (μCT) were used to measure alterations in articular cartilage and subchondral bone [BV(bone volume)/TV (tissue volume), Tb.Pf (trabecular pattern factor), Tb.N (trabecular number), SBP.Th(subchondral bone plate.Th), pSmad2/3, Nestin, and OARSI (Osteoarthritis Research Society International) scoring]. Results Knee OA models and drug administration devices in subchondral bone were successfully established in rats. Sham and HF+ACLT groups had greater subchondral BV/TV(0.381±0.060 mm3 and 0.322±0.060 mm3), SBP.Th (0.570±0.042 mm and 0.521±0.122 mm) and Tb.N (4.871±0.214 mm-1 and 4.364±0.466 mm-1) than Vehicle+ACLT group did (0.229±0.063) mm3, 0.324±0.165 mm and 2.978±0.804 mm-1, respectively); Sham and HF+ACLT groups had less subchondral Tb.Pf (-0.880±0.210 mm-1 and -0.377±0.259 mm-1), lower expression of pSmad2/3 (90.2±40.0 and 90.8±34.5) and Nestin (16.9±5.8 and 18.5±4.7) and OARSI scores (1.2±0.7 and 2.5±1.9) than Vehicle+ACLT group did (0.057±0.535 mm-1, 142.7±37.0, 25.9±7.4 and 5.4±2.8, respectively). All the above differences were statistically significant (P 0.05). Conclusion Subchondral administration of HF can inhibit TGF-β induced erroneous recruitment of mesenchymal stem cells in subchondral bone, thus attenuating OA progression. Key words: Osteoarthritis, knee; Transforming growth factor-β; Mesenchymal stem cells; Subchondral bone

Mesenchymal stem cell secretome reduces pain and prevents cartilage damage in a murine osteoarthritis model.

Mesenchymal stem cells (MSCs) represent a promising biological therapeutic option as an osteoarthritis (OA)-modifying treatment. MSCs secrete factors that can counteract inflammatory and catabolic processes and attract endogenous repair cells. The effects of intra-articular injection of MSC secretome on OA-related pain, cartilage damage, subchondral bone alterations and synovial inflammation were studied in a mouse collagenase-induced OA model. The MSC secretome was generated by stimulating human bone-marrow-derived MSCs with interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα). 54 mice were randomly assigned to injections with i) MSC secretome from 20,000 MSCs, ii) 20,000 MSCs or iii) medium (control). Pain was assessed by hind limb weight distribution. Cartilage damage, subchondral bone volume and synovial inflammation were evaluated by histology. MSC-secretome- and MSC-injected mice showed pain reduction at day 7 when compared to control mice. Cartilage damage was more abundant in the control group as compared to healthy knees, a difference which was not found in knees treated with MSC secretome or MSCs. No effects were observed regarding synovial inflammation, subchondral bone volume or the presence of different macrophage subtypes. Injection of MSC secretome, similarly to injection of MSCs, resulted in early pain reduction and had a protective effect on the development of cartilage damage in a murine OA model. By using the regenerative capacities of the MSC-secreted factors, it will be possible to greatly enhance the standardisation, affordability and clinical translatability of the approach. This way, this biological therapy could evolve towards a true disease-modifying anti-osteoarthritic drug.

Mitigation of Articular Cartilage Degeneration and Subchondral Bone Sclerosis in Osteoarthritis Progression Using Low-Intensity Ultrasound Stimulation

The purpose of this study was to evaluate the effect of low-intensity ultrasound on articular cartilage and subchondral bone alterations in joints under normal and functional disuse conditions during osteoarthritis (OA) progression. Total of thirty 5-mo-old female Sprague–Dawley rats were randomly assigned to six groups (n = 5/group): age-matched group, OA group, OA + ultrasound (US) group, hindlimb suspension (HLS) group, HLS + OA group and HLS + OA + US group. The surgical anterior cruciate ligament was used to induce OA in the right knee joints. After 2 wk of OA induction, low-intensity ultrasound generated with a 3-MHz transducer with 20% pulse duty cycle and 30 mW/cm2 acoustic intensity was delivered to the right knee joints for 20 min a day, 5 d a week for a total of 6 wk. Then, the right tibias were harvested for micro-computed tomography, histologic and mechanical analysis. Micro-computed tomography results indicated that the thickness and sulfated glycosaminoglycan content of cartilage decreased, but the thickness of the subchondral cortical bone plate and the formation of subchondral trabecular bone increased in the OA group under the normal joint use condition. Furthermore, histologic results revealed that chondrocyte density and arrangement in cartilage corrupted and the underlying subchondral bone increased during OA progression. These changes were accompanied by reductions in mechanical parameters in OA cartilage. However, fewer OA symptoms were observed in the HLS + OA group under the joint disuse condition. The cartilage degeneration and subchondral bone sclerosis were alleviated in the US treatment group, especially under normal joint use condition. In conclusion, low-intensity ultrasound could improve cartilage degeneration and subchondral sclerosis during OA progression. Also, it could provide a promising strategy for future clinical treatment for OA patients.

Longitudinal changes in subchondral bone structure as assessed with MRI are associated with functional outcome after high tibial osteotomy

ObjectivesThe primary objective of this study was to evaluate the effects of high tibial osteotomy (HTO) on subchondral bone structure assessed with MR-based trabecular bone imaging and the correlations of these effects with functional outcome and clinical symptoms.MethodsPatients with varus malalignment (6.2°±2.2°) and without a history of knee surgery (n=22; 3 women; 48.7±10.3 years) were included into this prospective study. 1.5T MRI was performed before and on average 1.5 years after HTO (amount of correction 4.7°±2.5°) and histomorphometric parameters of the trabecular bone were calculated for the medial/lateral tibia and femur. Functional outcome was assessed with validated scores focusing on sports activity including the Lysholm Score, Tegner Activity Scale and the adapted Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Score.ResultsApparent trabecular number significantly decreased in all compartments of the tibiofemoral joint when comparing values before and on average 1.5 years after HTO (p<0.05 for all). Decrease in apparent trabecular number was significantly higher within the medial tibia compared with the lateral compartment (mean difference −0.24 mm−1 (95% CI −0.33 to −0.14 mm−1); p<0.001). Apparent trabecular bone thickness significantly increased within 1.5 years after HTO in the lateral femur (p=0.002) and tibia (p<0.001). The Lysholm Score and Tegner Scale demonstrated an improvement of functional outcome, and the adapted WOMAC demonstrated an improvement of pain, stiffness and physical function within 1.5 years after HTO (p<0.01), with the improvement of WOMAC correlating significantly with changes in trabecular bone thickness within the medial tibia (r=−0.48; p=0.01).ConclusionThese findings indicate a reversal of the previous subchondral bone alterations in patients with varus malalignment after undergoing HTO, while pronounced subchondral changes were associated with a better functional outcome.Level of evidenceIII

Pathological Alterations of the Lumbar Facet Joint Subchondral Bone and Synovial Fold during Hypomobility Induced Cartilage Degeneration

Low back pain (LBP) is a leading cause of worldwide disability and socioeconomic burden. Degeneration of the lumbar facet joints (FJ) or spinal osteoarthritis (OA) is one clinically relevant source of LBP. Recent studies suggest that the increased prevalence of OA may be a result of not only overuse of a synovial joint but also less joint movement. A better understanding of how FJ degeneration is induced and progresses may provide the foundation to reveal the underlying mechanisms of spinal OA and LBP.OA is a whole joint disease involving several tissues. The avascular articular cartilage relies upon adjacent tissues to maintain its homeostasis. Of particular importance is the synovial fluid from the synovium that is largely responsible for nutrient supply and waste removal for the cartilage; this requires appropriate joint movement. When cartilage loses access to synovial fluid, vascular channel ingrowth into cartilage and neovascularization from the subchondral bone can occur to promote degeneration. Less joint movement (hypomobility) could contribute to OA through a similar process. Although previous studies implicated neovascularization in OA induction and progression in other joints, less is known in the FJ. It was reported that during spinal OA there were increased subchondral channels invading the FJ articular cartilage. Here, we used a preclinical rat model of spinal OA to examine lumbar FJ degeneration after hypomobility. Previously, we found that hypomobility in lumbar FJs leads to cartilage degeneration that mimics the location and progression of spinal OA. We also observed that the synovial fold (SF) regressed from the FJ cavity by 2 weeks after hypomobility in the same location as early cartilage degeneration. As synovium pathology can induce subchondral processes to promote degeneration, we examined the onset, location, and progression of subchondral vascular channels after hypomobility. We hypothesized that channels would increase in the cephalad regions of the FJ superior articular process (SAP) by 2 weeks after hypomobility adjacent to cartilage degeneration and SF regression. We performed histological analyses on brightfield microscopic images of sections from the cephalad and cephalad‐middle regions of bilateral L4/5 and L5/6 FJ in hypomobile and control rats at 1, 2, and 4 weeks. The tissues were formalin fixed, decalcified, paraffin embedded, transversely sectioned (45 μm), and stained with Ehrlich's hematoxylin and light green. Intra‐ and inter‐rater reliability was acceptable for channel counts (K = 0.88 &amp; 0.76) and a severity scale of vascular channel ingrowth (Kw = 0.81 &amp; 0.89). Spinal hypomobility was associated with significant increases in vascular channel counts and severity of cartilage invasion in the FJ SAP margins by 2 weeks. In hypomobile rats, we also observed changes to the appearance of blood vessels in the adjacent SF (increased numbers of enlarged &amp; disorganized vessels). These changes correlate with the onset and locations of SAP cartilage degeneration after hypomobility. Our findings mimic spinal OA and suggest a role for the subchondral bone and SF in FJ degeneration.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Osteoarthritis like Alteration of Cartilage and Subchondral Bone Induced by Protein Malnutrition is treated by Nutritional Essential Amino Acids Supplements

Osteoarthritis like Alteration of Cartilage and Subchondral Bone Induced by Protein Malnutrition is treated by Nutritional Essential Amino Acids Supplements

Subchondral bone in osteoarthritis: association between MRI texture analysis and histomorphometry.

Magnetic resonance imaging (MRI) texture analysis is a method of analyzing subchondral bone alterations in osteoarthritis (OA). The objective of this study was to evaluate the association between MR texture analysis and ground-truth subchondral bone histomorphometry at the tibial plateau. The local research ethics committee approved the study. All subjects provided written, informed consent. This was a cross-sectional study carried out at our institution between February and August 2014. Ten participants aged 57-84 with knee OA scheduled for total knee arthroplasty (TKA) underwent pre-operative MRI of the symptomatic knee at 3T using a high spatial-resolution coronal T1 weighted sequence. Tibial plateau explants obtained at the time of TKA underwent histological preparation to allow calculation of bone volume fraction (BV.TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp) and trabecular number (Tb.N). Texture analysis was performed on the tibial subchondral bone of MRI images matched to the histological sections. Regression models were created to assess the association of texture analysis features with BV.TV, Tb.Th, Tb.Sp and Tb.N. MRI texture features were significantly associated with BV.TV (R2=0.76), Tb.Th (R2=0.47), Tb.Sp (R2=0.75) and Tb.N (R2=0.60, all P<0.001). Simple gray-value histogram based texture features demonstrated the highest standardized regression coefficients for each model. MRI texture analysis features were significantly associated with ground-truth subchondral bone histomorphometry at the tibial plateau.

Optimizing finite element predictions of local subchondral bone structural stiffness using neural network-derived density-modulus relationships for proximal tibial subchondral cortical and trabecular bone

BackgroundQuantitative computed tomography based subject-specific finite element modeling has potential to clarify the role of subchondral bone alterations in knee osteoarthritis initiation, progression, and pain. However, it is unclear what density-modulus equation(s) should be applied with subchondral cortical and subchondral trabecular bone when constructing finite element models of the tibia. Using a novel approach applying neural networks, optimization, and back-calculation against in situ experimental testing results, the objective of this study was to identify subchondral-specific equations that optimized finite element predictions of local structural stiffness at the proximal tibial subchondral surface. MethodsThirteen proximal tibial compartments were imaged via quantitative computed tomography. Imaged bone mineral density was converted to elastic moduli using multiple density-modulus equations (93 total variations) then mapped to corresponding finite element models. For each variation, root mean squared error was calculated between finite element prediction and in situ measured stiffness at 47 indentation sites. Resulting errors were used to train an artificial neural network, which provided an unlimited number of model variations, with corresponding error, for predicting stiffness at the subchondral bone surface. Nelder-Mead optimization was used to identify optimum density-modulus equations for predicting stiffness. FindingsFinite element modeling predicted 81% of experimental stiffness variance (with 10.5% error) using optimized equations for subchondral cortical and trabecular bone differentiated with a 0.5g/cm3 density. InterpretationIn comparison with published density-modulus relationships, optimized equations offered improved predictions of local subchondral structural stiffness. Further research is needed with anisotropy inclusion, a smaller voxel size and de-blurring algorithms to improve predictions.