Properties Of Subchondral Bone Research Articles

PTH treatment before cyclic joint loading improves cartilage health and attenuates load-induced osteoarthritis development in mice.

Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the subchondral bone properties to OA development. We used parathyroid hormone (PTH) to modulate bone mass before OA initiation and alendronate (ALN) to inhibit bone remodeling during OA progression. We examined the spatiotemporal progression of joint damage by combining histopathological and transcriptomic analyses across joint tissues. The additive effect of PTH pretreatment before OA initiation and ALN treatment during OA progression most effectively attenuated load-induced OA pathology. Individually, PTH directly improved cartilage health and slowed the development of cartilage damage, whereas ALN primarily attenuated subchondral bone changes associated with OA progression. Joint damage reflected early transcriptomic changes. With both treatments, the structural changes were associated with early modulation of immunoregulation and immunoresponse pathways that may contribute to disease mechanisms. Overall, our results demonstrate the potential of subchondral bone-modifying therapies to slow the progression of OA.

Alterations in compositional and cellular properties of the subchondral bone are linked to cartilage degeneration in hip osteoarthritis

ObjectiveThe subchondral bone is an emerging regulator of osteoarthritis (OA). However, knowledge of how specific subchondral alterations relate to cartilage degeneration remains incomplete. MethodFemoral heads were obtained from 44 patients with primary OA during total hip arthroplasty and from 30 non-OA controls during autopsy. A multiscale assessment of the central subchondral bone region comprising histomorphometry, quantitative backscattered electron imaging, nanoindentation, and osteocyte lacunocanalicular network characterization was employed. ResultsIn hip OA, thickening of the subchondral bone coincided with a higher number of osteoblasts (controls: 3.7±4.5 mm-1, OA: 16.4±10.2 mm-1, age-adjusted mean difference 10.5 mm-1 [95% CI 4.7 to 16.4], p<0.001) but a similar number of osteoclasts compared to controls (p=0.150). Furthermore, higher matrix mineralization heterogeneity (CaWidth, controls: 2.8±0.2 wt%, OA: 3.1±0.3 wt%, age-adjusted mean difference 0.2 wt% [95% CI 0.1 to 0.4], p=0.011) and lower tissue hardness (controls: 0.69±0.06 GPa, OA: 0.67±0.06 GPa, age-adjusted mean difference -0.05 GPa [95% CI -0.09 to -0.01], p=0.032) were detected. While no evidence of altered osteocytic perilacunar/canalicular remodeling in terms of fewer osteocyte canaliculi was found in OA, specimens with advanced cartilage degeneration showed a higher number of osteocyte canaliculi and larger lacunocanalicular network area compared to those with low-grade cartilage degeneration. Multiple linear regression models indicated that several subchondral bone properties, especially osteoblast and osteocyte parameters, were closely related to cartilage degeneration (R2 adjusted=0.561, p<0.001). ConclusionSubchondral bone properties in OA are affected at the compositional, mechanical, and cellular levels. Based on their strong interaction with cartilage degeneration, targeting osteoblasts/osteocytes may be a promising therapeutic OA approach. Data and materials availabilityAll data are available in the main text or the supplementary materials.

Acupotomy ameliorates subchondral bone absorption and mechanical properties in rabbits with knee osteoarthritis by regulating bone morphogenetic protein 2-Smad1 pathway.

To investigate the effects of acupotomy on the subchondral bone absorption and mechanical properties in rabbits with knee osteoarthritis (KOA). The rabbits were divided into blank control, model, acupotomy and electroacupuncture (EA) groups, with 12 rabbits in each. Modified Videman's method was used to prepare KOA model. The acupotomy and EA group were given indicated intervention for 3 weeks. The behavior of rabbits in each group was recorded. Subsequently, cartilage-subchondral bone units were obtained and morphological changes were observed by optical microscope and micro computed tomography. Compression test was used to detect the mechanical properties of subchondral bone, Western blot and real-time polymerase chain reaction (RT-PCR) were applied to detect the expression of bone morphogenetic protein 2-Smad1 (BMP2-Smad1) pathway in subchondral bone. Compared with the control group, rabbits in the KOA group showed lameness, knee pain, and cartilage degradation; the subchondral bone showed active resorption, the mechanical properties decreased significantly and the BMP2-Smad1 pathway downregulated significantly. Both acupotomy and EA intervention could increase the thickness of trabecular bone (Tb. Th), the bone volume fraction (BV/TV) and the thickness of subchondral bone plate, reduce the separation of trabecular bone (Tb. Sp), improve the maximum load and elastic modulus of subchondral bone, and effectively delay cartilage degeneration in KOA rabbits. This process may be achieved through upregulation the related proteins of BMP2-Smad1 pathway. The maximum load and elastic modulus of subchondral bone in the acupotomy group were slightly better than those in the EA group. Acupotomy could effectively protect cartilage by inhibiting abnormal bone resorption and improving mechanical properties of subchondral bone thorough the related proteins of BMP2-Smad1 pathway in KOA rabbits.

Three-Dimensional Analysis of the Trapezium Subchondral Bone and its Association with Trapeziometacarpal Joint Osteoarthritis.

Subchondral bone properties are associated with the pathogenesis of osteoarthritis (OA), but this relationship has not been confirmed in the trapeziometacarpal joint (TMCJ). We aimed to evaluate the thickness (SBT) and density (SBD) of three-dimensional (3D) trapezium subchondral bone models derived from computed tomography (CT) images, and their relationships with early-stage TMCJ OA. We reviewed patients with a distal radius fracture who underwent conventional CT scans and such osteoporosis evaluations as bone mineral density (BMD) and bone turnover markers (BTMs). From 3D trapezium subchondral bone models, we measured SBT and SBD according to the OA stage and performed multivariate analyses to evaluate their associations with age, sex, body mass index, BMD, and BTMs. As results, a total of 156 patients (78 men and 78 age-matched women; mean age, 67 ± 10years) were analyzed. There were 30 (19%) with grade 0, 71 (45%) with grade 1, 13 (8%) with grade 2, and 42 (27%) with grade 3 TMCJ OA. SBT was significantly lower in patients with grade 1 OA than those with grade 0 or grade 3 OA, but SBD generally increased according to the OA severity. Low SBT was associated with low BMD, and low SBD with low BMD, high osteocalcin levels, and severe OA grades. In conclusion, patients with early-stage radiographic TMCJ OA have a lower SBT at the trapezium, which may support the potential role of subchondral bone in OA pathogenesis. This study also shows that subchondral bone properties are associated with BMD and osteocalcin levels.

Nanosilicate-Reinforced Silk Fibroin Hydrogel for Endogenous Regeneration of Both Cartilage and Subchondral Bone.

Osteochondral defects are characterized by injuries to both cartilage and subchondral bone, which is a result of trauma, inflammation, or inappropriate loading. Due to the unique biological properties of subchondral bone and cartilage, developing a tissue engineering scaffold that can promote dual-lineage regeneration of cartilage and bone simultaneously remains a great challenge. In this study, a microporous nanosilicate-reinforced enzymatically crosslinked silk fibroin (SF) hydrogel is fabricated by introducing montmorillonite (MMT) nanoparticles via intercalation chemistry. In vitro studies show that SF-MMT nanocomposite hydrogel has improved mechanical properties and hydrophilicity, as well as the bioactivities to promote the osteogenic differentiation of bone marrow mesenchymal stem cells and maintain chondrocyte phenotype compared with SF hydrogel. Global proteomic analysis verifies the dual-lineage bioactivities of SF-MMT nanocomposite hydrogel, which are probably regulated by multiple signaling pathways. Furthermore, it is observed that the biophysical interaction of cells and SF-MMT nanocomposite hydrogel is partially mediated by clathrin-mediated endocytosis and its downstream processes. In vivo, the SF-MMT nanocomposite hydrogel effectively promotes osteochondral regeneration as evidenced by macroscopic, micro-CT, and histological evaluation. In conclusion, a functionalized SF-MMT nanocomposite hydrogel is developed with dual-lineage bioactivity for osteochondral regeneration, indicating its potential in osteochondral tissue engineering.

Biomechanical and Microstructural Properties of Subchondral Bone From Three Metacarpophalangeal Joint Sites in Thoroughbred Racehorses.

Fatigue-induced subchondral bone (SCB) injury is common in racehorses. Understanding how subchondral microstructure and microdamage influence mechanical properties is important for developing injury prevention strategies. Mechanical properties of the disto-palmar third metacarpal condyle (MCIII) correlate poorly with microstructure, and it is unknown whether the properties of other sites within the metacarpophalangeal (fetlock) joint are similarly complex. We aimed to investigate the mechanical and structural properties of equine SCB from specimens with minimal evidence of macroscopic disease. Three sites within the metacarpophalangeal joint were examined: the disto-palmar MCIII, disto-dorsal MCIII, and proximal sesamoid bone. Two regions of interest within the SCB were compared, a 2 mm superficial and an underlying 2 mm deep layer. Cartilage-bone specimens underwent micro-computed tomography, then cyclic compression for 100 cycles at 2 Hz. Disto-dorsal MCIII specimens were loaded to 30 MPa (n = 10), while disto-palmar MCIII (n = 10) and proximal sesamoid (n = 10) specimens were loaded to 40 MPa. Digital image correlation determined local strains. Specimens were stained with lead-uranyl acetate for volumetric microdamage quantification. The dorsal MCIII SCB had lower bone volume fraction (BVTV), bone mineral density (BMD), and stiffness compared to the palmar MCIII and sesamoid bone (p < 0.05). Superficial SCB had higher BVTV and lower BMD than deeper SCB (p < 0.05), except at the palmar MCIII site where there was no difference in BVTV between depths (p = 0.419). At all sites, the deep bone was stiffer (p < 0.001), although the superficial to deep gradient was smaller in the dorsal MCIII. Hysteresis (energy loss) was greater superficially in palmar MCIII and sesamoid (p < 0.001), but not dorsal MCIII specimens (p = 0.118). The stiffness increased with cyclic loading in total cartilage-bone specimens (p < 0.001), but not in superficial and deep layers of the bone, whereas hysteresis decreased with the cycle for all sites and layers (p < 0.001). Superficial equine SCB is uniformly less stiff than deeper bone despite non-uniform differences in bone density and damage levels. The more compliant superficial layer has an important role in energy dissipation, but whether this is a specific adaptation or a result of microdamage accumulation is not clear.

Early Emergent and Progressive Aberrant Subchondral Bone Remodeling Coupled with Aggravated Cartilage Degeneration in Developmental Dysplasia of the Hip.

ObjectiveDevelopmental dysplasia of the hip (DDH) is the most common skeletal development in children and could result in secondary osteoarthritis. This study aims to clarify the alternations of subchondral trabecular bone remodeling and microstructural properties during the development of DDH, and the potential influence of these alternations on the overlying cartilage degeneration and DDH progression.DesignTraditional straight-leg swaddling method was adopted to establish DDH model in newborn Sprague Dawley rats. Hip joint specimens from normal or DDH rats were used. Typical features of DDH in radiological examination were observed by x-ray analysis. Micro–computed tomography analysis was applied to evaluate the microstructural properties of subchondral bone at postnatal weeks 2, 4, and 6. Histological and immunohistochemical analyses were adopted to appraise subchondral bone remodeling activity and cartilage degeneration. The associations among subchondral bone, articular cartilage, and DDH severity were analyzed via multiple linear regression analysis.ResultsCompared with control group, the subchondral bone in DDH group displayed a gradual trend of deteriorated microstructure and worsening biomechanical properties along with aberrant bone remodeling, which might be responsible for the inhibition of stress transmission from the articular cartilage to the subchondral bone and thus leading to the cartilage degeneration and accelerated DDH progression.ConclusionsOur findings indicate that alternations of subchondral trabecular bone in a time-dependent manner could contribute to the DDH progression and the amelioration on subchondral bone might be a favorable therapeutic candidate for DDH.

Can CD200R1 Agonists Slow the Progression of Osteoarthritis Secondary to Injury?

Post-traumatic knee osteoarthritis is characterized by cartilage degeneration, subchondral bone remodeling, osteophyte formation, and synovial changes. Therapeutic targeting of inflammatory activity in the knee immediately post injury may alter the course of osteoarthritis development. This study aimed to determine whether CD200R1 agonists, namely the protein therapeutic CD200Fc or the synthetic DNA aptamer CCS13, both known to act as anti-inflammatory agents, are able to delay the pathogenesis of injury-associated knee osteoarthritis in a murine model. Ten week old male C57BL/6 mice were randomized and surgical destabilization of the medial meniscus (DMM) to induce knee arthritis or sham surgery as a control were performed. CCS13 was evaluated as a therapeutic treatment along with CD200Fc and a phosphate-buffered saline vehicle control. Oligonucleotides were injected intra-articularly beginning one week after surgery, with a total of six injections administered prior to sacrifice at 12 weeks post-surgery. Histopathological assessment was used as the primary outcome measure to assess cartilage and synovial changes, while µCT imaging was used to compare the changes to the subchondral bone between untreated and treated arthritic groups. We did not find any attenuation of cartilage degeneration or synovitis in DMM mice with CD200Fc or CCS13 at 12 weeks post-surgery, nor stereological differences in the properties of subchondral bone. The use of CD200R1 agonists to blunt the inflammatory response in the knee are insufficient to prevent disease progression in the mouse DMM model of OA without anatomical restoration of the normal joint biomechanics.

BONE-MUSCLE-FAT INTERACTIONS AND PERFUSIVE EVIDENCE OF INFLAMMATION IN NON-OVERWEIGHT POSTMENOPAUSAL WOMEN WITH EARLY KNEE OA

Postmenopausal women are affected by a decline of estrogen resulting in an established insult on bone (loss), muscle (loss), and fat (gain). These effects are likely not limited to central sites. We were interested in potential damage to the knee in this process and how it contributes to known phenotypes observed in osteoarthritis within this population of women. To glean evidence of inflammation, we investigated perfusion kinetics within periarticular bone, muscle, and fat tissues. To investigate how periarticular muscle and fat relate to subchondral bone properties; and to understand how perfusion may mediate these relationships. This was a cross-sectional study of 52 postmenopausal women recruited by convenience sampling at the University Health Network (Toronto). Women 60-85 years old with evidence of knee pain were included if their BMI upon screening was <=25 kg/m 2 and had no renal disease or contraindications to MRI or Gadolinium for Dynamic Contrast-Enhanced (DCE)-MRI. Time resolution on DCE-MRI scans was 7 ms and Toft's pharmacokinetic model was used to estimate perfusion rate, Kep, within each knee compartment and the infrapatellar fat pad (IPFP) using Tissue4D (Siemens) (Fig 1). Periarticular inter- and intramuscular fat (IMF) was segmented on transaxial proton-density weighted MRI using the iterative threshold-seeking algorithm (ITSA) in Python (Fig 2). Subchondral BMD, periarticular muscle mass, and IPFP content were quantified from compartment-specific pQCT scans at 200 µm in-plane pixel size on Stratec software (Fig 3). Where relevant, compartment-specific associations were obtained using general linear or logistic regression models, adjusting for age and BMI at minimum, with 95% confidence. A lower periarticular (calf side) muscle mass (b= -0.58(-1.02,-0.15)per 1mg) and density (b= -2.76(-5.35,-0.17)per 1mg/cc) was significantly associated with higher medial and lateral (b= -4.57(-7.21,-1.93)per 1mg/cc) subchondral BMD (mg/cc) of the tibia. While the directionality was similar for MR measures of IMF on the calf side, it was only marginally significant. In contrast, a higher IMF volume on the thigh side was associated with lower subchondral BMD of medial femoral (b= -2.39(-4.09,-0.69)) and tibial (b= -1.58(-3.05,-0.11)) compartments. Both higher periarticular IMF(MRI) and lower muscle mass(CT) were correlates of greater perfusion (Kep) of the lateral tibia (b= 1.69 to 2.88 per 1unit, p<0.02). Correspondingly, a higher perfusion of the lateral tibia(b=1.25(0.34,2.15)) was associated with a co-localized higher subchondral BMD. On the other hand, greater perfusion in the IPFP was related to a lower co-localized subchondral BMD (b= -1.70 to -2.22, p<0.01). Although no formal mediation analysis was performed in this smaller pre-pandemic sample, there is evidence to suggest that periarticular muscle and fat may influence subchondral bone by triggering nearby inflammation. The translated effects appear to differ - with correlates on the calf/tibia side resulting in higher BMD, and correlates on the thigh/femur side resulting in lower BMD. It is possible that the observed tibial BMD may reflect the beginning of a collapsing architecture. CIHR PJT156274. Arthritis Society Ken Smith Stars Career Development Award. None of the authors have disclosures. CORRESPONDENCE ADDRESS: andy.wong@uhnresearch.ca

Subchondral Bone Microarchitectural and Mineral Properties and Expression of Key Degradative Proteinases by Chondrocytes in Human Hip Osteoarthritis.

Background: The purpose of this study was to investigate the relationship between the expression of key degradative enzymes by chondrocytes and the microarchitectural and mineral properties of subchondral bone across different stages of cartilage degradation in human hip osteoarthritis (OA). Methods: Osteochondral samples at different stages of cartilage degradation were collected from 16 femoral heads with OA. Osteochondral samples with normal cartilage were collected from seven femoral heads with osteoporosis. Microcomputed tomography was used for the investigation of subchondral bone microarchitecture and mineral densities. Immunohistochemistry was used to study the expression and distribution of MMP13 and ADAMTS4 in cartilage. Results: The microarchitecture and mineral properties of the subchondral plate and trabecular bone in OA varied with the severity of the degradation of the overlying cartilage. Chondrocytes expressing MMP13 and ADAMTS4 are mainly located in the upper zone(s) of cartilage regardless of the histopathological grades. The zonal expression of these enzymes in OA (i.e., the percentage of positive cells in the superficial, middle, and deep zones), rather than their overall expression (the percentage of positive cells in the full thickness of the cartilage), exhibited significant variation in relation to the severity of cartilage degradation. The associations between the subchondral bone properties and zonal and overall expression of these enzymes in the cartilage were generally weak or nonsignificant. Conclusions: Phenotypic changes in chondrocytes and remodelling of subchondral bone proceed at different rates throughout the process of cartilage degradation. Biological influences are more important for cartilage degradation at early stages, while biomechanical damage to the compromised tissue may outrun the phenotypic change of chondrocytes and is critical in the advanced stages.

Diabetes mellitus accelerates the progression of osteoarthritis in streptozotocin-induced diabetic mice by deteriorating bone microarchitecture, bone mineral composition, and bone strength of subchondral bone.

BackgroundThe purpose of this study was to develop an optimal diabetes-osteoarthritis (DM-OA) mouse model to validate that diabetes aggravates osteoarthritis (OA) and to evaluate the microarchitecture, chemical composition, and biomechanical properties of subchondral bone (SB) as a consequence of the DM-OA-induced damage induced.MethodsMice were randomly divided into three groups: DM-OA group, OA group, and sham group. Blood glucose levels, body weight, and food intake of all animals were recorded. Serum calcium (Ca) and osteocalcin (OCN) levels were compared in the three groups. The messenger ribonucleic acid (mRNA) and protein expression of key regulators for bone metabolism were detected. A semi-quantitative grading system [Osteoarthritis Research Society International (OARSI)] was used to evaluate cartilage and SB degeneration. Microspectroscopy, microindentations, micro-computed tomography (CT) imaging, and fracture load of compression testing were also used to evaluate trabecular SB properties.ResultsGlycemic monitoring and pancreas pathological results indicated stable high blood glucose and massive destruction of pancreas and islet cells in the DM-OA group. Serum levels of bone specific alkaline phosphatase (ALP-B) and tartrate-resistant acid phosphatase 5b (TRACP-5b) in the DM-group were higher than those of the other two groups while levels of serum Ca and OCN were lower. Meanwhile, the protein and mRNA expression of osteoblast-specific biomarkers [osteoprotegerin/receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) ratio, collagen type I (COL-I), Runt-related transcription factor 2 (RUNX-2), OCN] were suppressed, and osteoclast-specific biomarkers [sclerostin (SOST)] was elevated in the DM-OA group. The mineral-to-collagen ratio, microindentation elastic modulus, hardness, micro-architectural parameters, bone mineral density, and fracture load of SB trabecular bone of the DM-OA group joint were lower than those of the other two groups. On the other hand, The OARSI score, trabecular spacing, and structural model index of the DM-OA group joint were higher than those of the other two groups.ConclusionsThe glycemic and pancreatic pathological results indicated that the DM-OA model was a simple and reliable model induced by streptozotocin (STZ) and surgery. The results revealed the mechanisms through which diabetes accelerates OA; that is, by damaging and deteriorating the functions of SB, including its microarchitecture, chemical composition, and biomechanical properties.

Microstructure and mechanical properties of subchondral bone are negatively regulated by tramadol in osteoarthritis in mice.

Objectives: In the treatment of osteoarthritis (OA), tramadol, a common weak opioid, has become popular due to its effectiveness in inhibition of pain. In the present study, we aimed to explore the effect of tramadol on subchondral bone, especially changes in the microstructure and mechanical properties.Methods: A mouse model of OA was established in the present study by destabilization of the medial meniscus (DMM). A vehicle or drug was administered for 4 weeks. Specimens were harvested and analyzed radiologically and histologically using micro-computed tomography (micro-CT), scanning electron microscopy (SEM), atomic force microscopy (AFM) and histological staining to evaluate the knee joints of mice undergoing different forms of intervention.Results: In the early stages of OA induced by DMM, the subchondral bone volume fraction in the OA group was significantly higher than in the sham+vehicle (sham+veh) group, while the volume in the treatment groups was lower than in the DMM+vehicle (DMM+veh) and sham+veh groups. In addition, the elastic moduli in the treatment groups clearly decreased compared with the DMM+veh and sham+veh groups. Observations of the subchondral bone surface by SEM indicated serious destruction, principally manifesting as a decrease in lacunae and more numerous and scattered cracks. Histological staining demonstrated that there was no difference in the degeneration of either the articular cartilage or synovial cells whether tramadol was used or not.Conclusion: Although tramadol is effective in inhibiting pain in early OA, it negatively regulates the microstructure and mechanical properties of subchondral bone in joints.

Age-related changes of micro-morphological subchondral bone properties in the healthy femoral head

Alterations in the subchondral bone (SCB) are likely to play a decisive role in the development of osteoarthritis (OA). Since aging represents a major risk factor for OA, the aim of the current study was to assess the microstructural changes of the subchondral bone in the femoral head during aging. Femoral heads and matched iliac crest biopsies of 80 individuals (age 21-99 years) were collected post-mortem. The bone microstructure of the subchondral trabecular bone as well as the cartilage thickness (Cg.Th) and subchondral bone plate thickness (SCB.Th) were quantified using histomorphometry. The different subregions of the SCB were also imaged by quantitative backscattered electron imaging (qBEI) in 31 aged cases to assess the bone mineral density distribution (BMDD). The detected linear decline of bone volume per tissue volume (BV/TV) in the femoral head with aging (Slope, 95% CI:-0.208 to-0.109 %/yr.) was primarily due to a decrease in trabecular thickness (Tb.Th, Slope, 95% CI:-0.774 to-0.343μm/yr). While SCB.Th declined with aging (Slope, 95% CI:-1.941 to-0.034μm/yr), no changes in Cg.Th were detected (Slope, 95% CI:-0.001 to 0.005mm/yr). The matrix mineralization of the subchondral bone was lower compared to the trabecular bone and also decreased with aging. Regular changes of the SCB during aging primarily involve a reduction of Tb.Th, SCB.Th and matrix mineralization. Our findings facilitate future interpretations of early and late OA specimens to decipher the role of the SCB in OA pathogenesis.

Etoricoxib decreases subchondral bone mass and attenuates biomechanical properties at the early stage of osteoarthritis in a mouse model

Etoricoxib, a selective Cyclooxygenase-2 (COX-2) inhibitor, is commonly used in osteoarthritis (OA) for pain relief, however, little is known about the effects on subchondral bone. In the current study, OA was induced via destabilization of the medial meniscus (DMM) in C57BL/6 mice. Two days after surgery, mice were treated with different concentrations of Etoricoxib. Four weeks after treatment, micro computed tomography (Micro-CT) analysis, histological analysis, atomic force microscopy (AFM) analysis, and scanning electron microscopy (SEM) were performed to evaluate OA progression. We demonstrated that Etoricoxib inhibited osteophyte formation in the subchondral bone. However, it also reduced the bone volume fraction (BV/TV), lowered trabecular thickness (Tb.Th), and more microfractures and pores were observed in the subchondral bone. Moreover, Etoricoxib reduced the elastic modulus of subchondral bone. Exposure to Etoricoxib further increased the empty/total osteocyte ratio of the subchondral bone. Etoricoxib did not show significant improvement in articular cartilage destruction and synovial inflammation in early OA. Together, our observations suggested that although Etoricoxib can relieve OA-induced pain and inhibit osteophyte formation in the subchondral bone, it can also change the microstructures and biomechanical properties of subchondral bone, promote subchondral bone loss, and reduce subchondral bone quality in early OA mice.

Articular Cartilage Degradation and Aberrant Subchondral Bone Remodeling in Patients with Osteoarthritis and Osteoporosis.

Osteoarthritis (OA) and osteoporosis (OP) are two skeletal disorders associated with joint structures. Occasionally, OA and OP occur in the same patient. However, the effect of OP changes on OA progression in patients with osteoporotic OA (OP-OA) has not been reported, especially the potential association between subchondral bone and articular cartilage. Thus we investigated the alterations in the microstructure, biomechanical properties, and remodeling of subchondral bone as well as their association with cartilage damage in the hip joint of patients with OP-OA. Thirty-nine femoral head specimens were obtained from patients who underwent total hip arthroplasty (OA group, n = 19; OP-OA group, n = 20), and healthy specimens from cadaver donors were used (control group, n = 10). The microstructure and biomechanical properties of subchondral bone were evaluated by micro-computed tomography and micro-finite-element analysis. Histology, histomorphometric measurements, and immunohistochemistry were used to assess subchondral bone remodeling and cartilage damage. Linear regression analysis was performed to elucidate the relationship between subchondral bone and articular cartilage. In the subchondral bone of the OP-OA group, compared with that of the OA group, aberrant bone remodeling leads to an inferior microstructure and worsening biomechanical properties, potentially affecting transmission of loading stress from the cartilage to the subchondral bone, and then resulting in accelerated OA progression in patients with OP-OA. The results indicate that changes in subchondral bone could affect OA development and the improvement in subchondral bone with bone-metabolism agents may help mitigate OA progression when OP and OA coexist in the same patients. © 2019 American Society for Bone and Mineral Research.

Characterizing human subchondral bone properties using near-infrared (NIR) spectroscopy

Degenerative joint conditions are often characterized by changes in articular cartilage and subchondral bone properties. These changes are often associated with subchondral plate thickness and trabecular bone morphology. Thus, evaluating subchondral bone integrity could provide essential insights for diagnosis of joint pathologies. This study investigates the potential of optical spectroscopy for characterizing human subchondral bone properties. Osteochondral samples (n = 50) were extracted from human cadaver knees (n = 13) at four anatomical locations and subjected to NIR spectroscopy. The samples were then imaged using micro-computed tomography to determine subchondral bone morphometric properties, including: plate thickness (Sb.Th), trabecular thickness (Tb.Th), volume fraction (BV/TV), and structure model index (SMI). The relationship between the subchondral bone properties and spectral data in the 1st (650–950 nm), 2nd (1100–1350 nm) and 3rd (1600–1870 nm) optical windows were investigated using partial least squares (PLS) regression multivariate technique. Significant correlations (p < 0.0001) and relatively low prediction errors were obtained between spectral data in the 1st optical window and Sb.Th (R2 = 92.3%, error = 7.1%), Tb.Th (R2 = 88.4%, error = 6.7%), BV/TV (R2 = 83%, error = 9.8%) and SMI (R2 = 79.7%, error = 10.8%). Thus, NIR spectroscopy in the 1st tissue optical window is capable of characterizing and estimating subchondral bone properties, and can potentially be adapted during arthroscopy.

Stiffness and energy dissipation across the superficial and deeper third metacarpal subchondral bone in Thoroughbred racehorses under high-rate compression.

Subchondral bone injury due to high magnitude and repetition of compressive loading is common in humans and athletic animals such as Thoroughbred racehorses. Repeated loading of the joint surface may alter the subchondral bone microstructure and initiate microdamage in the bone adjacent to the articular cartilage. Understanding the relationship between microdamage, microstructure and mechanical properties of the subchondral bone adjacent to the articular cartilage is, therefore, essential in understanding the mechanism of subchondral bone injury. In this study, we used high-resolution µCT scanning, a digital image-based strain measurement technique, and mechanical testing to evaluate the three-dimensional pre-existing microcracks, bone volume fraction (BVF) and bone mineral density (BMD), and mechanical properties (stiffness and hysteresis) of subchondral bone (n = 10) from the distopalmar aspect of the third metacarpal (MC3) condyles of Thoroughbred racehorses under high-rate compression. We specifically compared the properties of two regions of interest in the subchondral bone: the 2 mm superficial subchondral bone (SSB) and its underlying 2 mm deep subchondral bone (DSB). The DSB region was 3.0 ± 1.2 times stiffer than its overlying SSB, yet it dissipated much less energy compared to the SSB. There was no correlation between structural properties (BVF and BMD) and mechanical properties (stiffness and energy loss), except for BMD and energy loss in SSB. The lower stiffness of the most superficial subchondral bone in the distal metacarpal condyles may protect the overlying cartilage and the underlying subchondral bone from damage under the high-rate compression experienced during galloping. However, repeated high-rate loading over time has the potential to inhibit bone turnover and induce bone fatigue, consistent with the high prevalence of subchondral bone injury and fractures in athletic humans and racehorses.

Electromechanical properties of human osteoarthritic and asymptomatic articular cartilage are sensitive and early detectors of degeneration.

To evaluate cross-correlations of exvivo electromechanical properties with cartilage and subchondral bone plate thickness, as well as their sensitivity and specificity regarding early cartilage degeneration in human tibial plateau. Six pairs of tibial plateaus were assessed exvivo using an electromechanical probe (Arthro-BST) which measures a quantitative parameter (QP) reflecting articular cartilage compression-induced streaming potentials. Cartilage thickness was then measured with an automated thickness mapping technique using Mach-1 multiaxial mechanical tester. Subsequently, a visual assessment was performed by an experienced orthopedic surgeon using the International Cartilage Repair Society (ICRS) grading system. Each tibial plateau was finally evaluated with μCT scanner to determine the subchondral-bone plate thickness over the entire surface. Cross-correlations between assessments decreased with increasing degeneration level. Moreover, electromechanical QP and subchondral-bone plate thickness increased strongly with ICRS grade (ρ=0.86 and ρ=0.54 respectively), while cartilage thickness slightly increased (ρ=0.27). Sensitivity and specificity analysis revealed that the electromechanical QP is the most performant to distinguish between different early degeneration stages, followed by subchondral-bone plate thickness and then cartilage thickness. Lastly, effect sizes of cartilage and subchondral-bone properties were established to evaluate whether cartilage or bone showed the most noticeable changes between normal (ICRS 0) and each early degenerative stage. Thus, the effect sizes of cartilage electromechanical QP were almost twice those of the subchondral-bone plate thickness, indicating greater sensitivity of electromechanical measurements to detect early osteoarthritis. The potential of electromechanical properties for the diagnosis of early human cartilage degeneration was highlighted and supported by cartilage thickness and μCT assessments.

Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice.

Animal models recapitulating post-traumatic osteoarthritis (OA) suggest that subchondral bone (SCB) properties and remodeling may play major roles in disease initiation and progression. Thus, we investigated the role of SCB properties and its effects on load-induced OA progression by applying a tibial loading model on two distinct mouse strains treated with alendronate (ALN). Cyclic compression was applied to the left tibia of 26-week-old male C57Bl/6 (B6, low bone mass) and FVB (high bone mass) mice. Mice were treated with ALN (26μg/kg/day) or vehicle (VEH) for loading durations of 1, 2, or 6 weeks. Changes in articular cartilage and subchondral and epiphyseal cancellous bone were analyzed using histology and microcomputed tomography. FVB mice exhibited thicker cartilage, a thicker SCB plate, and higher epiphyseal cancellous bone mass and tissue mineral density than B6 mice. Loading induced cartilage pathology, osteophyte formation, and SCB changes; however, lower initial SCB mass and stiffness in B6 mice did not attenuate load-induced OA severity compared to FVB mice. By contrast, FVB mice exhibited less cartilage damage, and slower-growing and less mature osteophytes. In B6 mice, inhibiting bone remodeling via ALN treatment exacerbated cartilage pathology after 6 weeks of loading, while in FVB mice, inhibiting bone remodeling protected limbs from load-induced cartilage loss. Intrinsically lower SCB properties were not associated with attenuated load-induced cartilage loss. However, inhibiting bone remodeling produced differential patterns of OA pathology in animals with low compared to high SCB properties, indicating that these factors do influence load-induced OA progression.

Sex dependent mechanical properties of the human mandibular condyle

The mandibular condyle consists of articular cartilage and subchondral bone that play an important role in bearing loads at the temporomandibular joint (TMJ) during static occlusion and dynamic mastication. The objective of the current study was to examine effects of sex and cartilage on 1) static and dynamic mechanical analysis (DMA) based dynamic energy storage and dissipation for the cartilage-subchondral bone construct of the human mandibular condyle, and 2) their correlations with the tissue mineral density and trabecular morphological parameters of subchondral bone. Cartilage-subchondral bone constructs were obtained from 16 individual human cadavers (9 males, 7 females, 79.00±13.10 years). After scanning with micro-computed tomography, the specimens were subjected to a non-destructive compressive static loading up to 7N and DMA using a cyclic loading profile (−5±2N at 2Hz). After removing the cartilage from the same specimen, the series of loading experiments were repeated. Static stiffness (K) and energy dissipation (W), and dynamic storage (K′), loss (K′′) stiffness, and energy dissipation (tan δ) were assessed. Gray values, which are proportional to degree of bone mineralization, and trabecular morphological parameters of the subchondral bone were also measured. After removal of the cartilage, static energy dissipation significantly decreased (p<0.009) but dynamic energy dissipation was not influenced (p>0.064). Many subchondral bone properties were significantly correlated with the overall mechanical behavior of the cartilage-subchondral bone constructs for males (p<0.047) but not females (p>0.054). However, after removal of cartilage from the constructs, all of the significant correlations were no longer found (p>0.057). The current findings indicate that the subchondral bone is responsible for bearing static and dynamic loading in males but not in females. This result indicates that the female condyle may have a mechanically disadvantageous TMJ loading environment.