Aim: To compare the genetic contribution to osteoarthritis (OA) vs other rheumatic/musculoskeletal diseases (RMDs) in the same population, and 2) to explore the role for any shared genetics between OA and other RMDs.
Methods: In 59 970 Swedish twins aged 35 years or older, we estimated the heritability (the variance explained by genetic factors) to OA in peripheral joints, back and neck pain, shoulder pain (adhesive capsulitis, impingement syndrome, etc), rheumatoid arthritis (RA), spondyloarthritis and psoriatic arthritis (SpA/PSA), myalgia and osteoporosis diagnosed in specialist and inpatient care. We also studied how much of covariance between OA and each of the RMDs could be explained by genetics, by studying phenotypic correlations in bivariate classical twin models.
Results: Any-site OA and hip OA (50% and 64%) were among the most heritable RMDs (as compared to 23% for fibromyalgia (lowest) and 63% for spondylarthritis (highest)). The highest phenotypic correlations were between OA (any joint site) and shoulder pain in the same individual (r=0.33, 95% CI=0.31-0.35), of which 70% (52-88) could be explained by shared genetics. The phenotypic correlation between OA and back/neck pain was r=0.25, with 25%-75% explained by genetics. Phenotypic correlations between OA and each of the other RMDs were lower (r~0.1 to r~0.2) with inconclusive sources of variation.
Conclusions: OA has relatively large heritability as compared to other RMDs. The co-existence of OA and shoulder pain, as well as back pain, was common and could often be explained by genetic factors. Findings imply similar etiologies of OA and several pain conditions.

Synovial fluid (SF) may contain cleavage products of proteolytic activities. Our aim was to characterize the degradome through analysis of proteolytic activity and differential abundance of these components in a peptidomic analysis of SF in knee osteoarthritis (OA) patients versus controls (n = 23). SF samples from end-stage knee osteoarthritis patients undergoing total knee replacement surgery and controls, that is, deceased donors without known knee disease were previously run using liquid chromatography mass spectrometry (LC-MS). This data was used to perform new database searches generating results for non-tryptic and semi-tryptic peptides for studies of degradomics in OA. We used linear mixed models to estimate differences in peptide-level expression between the two groups. Known proteolytic events (from the MEROPS peptidase database) were mapped to the dataset, allowing the identification of potential proteases and which substrates they cleave. We also developed a peptide-centric R tool, proteasy, which facilitates analyses that involve retrieval and mapping of proteolytic events. We identified 429 differentially abundant peptides. We found that the increased abundance of cleaved APOA1 peptides is likely a consequence of enzymatic degradation by metalloproteinases and chymase. We identified metalloproteinase, chymase, and cathepsins as the main proteolytic actors. The analysis indicated increased activity of these proteases irrespective of their abundance.

Objectives: Evaluate the natural course of anterior cruciate ligament (ACL) healing on MRI within 5 years of acute ACL rupture and compare 2-year and 5-year outcomes based on healing status and treatment group.
Methods: Secondary analysis of 120 Knee Anterior Cruciate Ligament Nonsurgical vs Surgical Treatment (KANON) trial participants randomised to rehabilitation and optional delayed ACL reconstruction (ACLR) or early ACLR and rehabilitation. ACL continuity on MRI (Anterior Cruciate Ligament OsteoArthritis Score 0-2) was considered evidence of ACL healing. Outcomes included Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS patient acceptable symptomatic state (PASS) and treatment failure criteria. Linear mixed models were used to estimate adjusted mean differences (95% CIs) in patient-reported sport and recreational function (KOOS-Sport/Rec) and quality of life (KOOS-QOL) at 2 and 5 years, between participants with MRI evidence of ACL healing and those who had (1) no evidence of ACL healing, (2) delayed ACLR or (3) early ACLR.
Results: MRI evidence of ACL healing at 2-year follow-up was observed in 16 of 54 (30%, 95% CI 19 to 43%) participants randomised to optional delayed ACLR. Excluding participants who had delayed ACLR, 16 of 30 (53%, 36-70%) participants managed with rehabilitation-alone displayed MRI evidence of ACL healing. Two-year outcomes were better in the healed ACL group (n=16) compared with the non-healed (n=14) (mean difference (95% CI) KOOS-Sport/Rec: 25.1 (8.6-41.5); KOOS-QOL: 27.5 (13.2-41.8)), delayed ACLR (n=24) (KOOS-Sport/Rec: 24.9 (10.2-39.6); KOOS-QOL: 18.1 (5.4-30.8)) and early ACLR (n=62) (KOOS-Sport/Rec: 17.4 (4.1-30.7); KOOS-QOL: 11.4 (0.0-22.9)) groups. Five-year KOOS-QOL was better in the healed versus non-healed group (25.3 (9.4-41.2)). Of participants with MRI evidence of ACL healing, 63-94% met the PASS criteria for each KOOS subscale, compared with 29-61% in the non-healed or reconstructed groups.
Conclusions: MRI appearance of ACL healing after ACL rupture occurred in one in three adults randomised to initial rehabilitation and one in two who did not cross-over to delayed ACLR and was associated with favourable outcomes. The potential for spontaneous healing of the ACL to facilitate better clinical outcomes may be greater than previously considered.

Objective: To investigate the feasibility of synchrotron radiation-based phase contrast enhanced micro-computed tomography (SR-PhC-μCT) for imaging of human meniscus. Quantitative parameters related to fiber orientation and crimping were evaluated as potential markers of tissue degeneration.
Design: Human meniscus specimens from 10 deceased donors were prepared using different preparation schemes: fresh frozen and thawed before imaging or fixed and paraffin-embedded. The samples were imaged using SR-PhC-μCT with an isotropic voxel size of 1.625 μm. Image quality was evaluated by visual inspection and spatial resolution. Fiber voxels were defined using a grey level threshold and a structure tensor analysis was applied to estimate collagen fiber orientation. The area at half maximum (FAHM) was calculated from angle histograms to quantify orientation distribution. Crimping period was calculated from the power spectrum of image profiles of crimped fibers. Parameters were compared to degenerative stage as evaluated by Pauli histopathological scoring.
Results: Image quality was similar between frozen and embedded samples and spatial resolutions ranged from 5.1 to 5.8 μm. Fiber structure, including crimping, was clearly visible in the images. Fibers appeared to be less organized closer to the tip of the meniscus. Fiber density might decrease slightly with degeneration. FAHM and crimping period did not show any clear association with histopathological scoring.
Conclusion: SR-PhC-μCT is a feasible technique for high-resolution 3D imaging of fresh frozen meniscus tissue. Further work is needed to establish quantitative parameters that relate to tissue degeneration, but this imaging technique is promising for future studies of meniscus structure and biomechanical response.

Osteoarthritis (OA) is the most common joint disease, where articular cartilage degradation is often accompanied with sclerosis of the subchondral bone. However, the association between OA and tissue mineralization at the nanostructural level is currently not understood. In particular, it is technically challenging to study calcified cartilage, where relevant but poorly understood pathological processes such as tidemark multiplication and advancement occur. Here, we used state-of-the-art microfocus small-angle X-ray scattering with a 5-μm spatial resolution to determine the size and organization of the mineral crystals at the nanostructural level in human subchondral bone and calcified cartilage. Specimens with a wide spectrum of OA severities were acquired from both medial and lateral compartments of medial compartment knee OA patients (n = 15) and cadaver knees (n = 10). Opposing the common notion, we found that calcified cartilage has thicker and more mutually aligned mineral crystals than adjoining bone. In addition, we, for the first time, identified a well-defined layer of calcified cartilage associated with pathological tidemark multiplication, containing 0.32 nm thicker crystals compared to the rest of calcified cartilage. Finally, we found 0.2 nm thicker mineral crystals in both tissues of the lateral compartment in OA compared with healthy knees, indicating a loading-related disease process because the lateral compartment is typically less loaded in medial compartment knee OA. In summary, we report novel changes in mineral crystal thickness during OA. Our data suggest that unloading in the knee might be involved with the growth of mineral crystals, which is especially evident in the calcified cartilage.

The underlying molecular mechanisms in osteoarthritis (OA) development are largely unknown. This study explores the proteome and the pairwise interplay of proteins in synovial fluid from patients with late-stage knee OA (arthroplasty), early knee OA (arthroscopy due to degenerative meniscal tear), and from deceased controls without knee OA. Synovial fluid samples were analyzed using state-of-the-art mass spectrometry with data-independent acquisition. The differential expression of the proteins detected was clustered and evaluated with data mining strategies and a multilevel model. Group-specific slopes of associations were estimated between expressions of each pair of identified proteins to assess the co-expression (i.e., interplay) between the proteins in each group. More proteins were increased in early-OA versus controls than late-stage OA versus controls. For most of these proteins, the fold changes between late-stage OA versus controls and early-stage OA versus controls were remarkably similar suggesting potential involvement in the OA process. Further, for the first time, this study illustrated distinct patterns in protein co-expression suggesting that the interplay between the protein machinery is increased in early-OA and lost in late-stage OA. Further efforts should focus on earlier stages of the disease than previously considered.

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

Purpose: To investigate the impact of COVID-19 in Sweden on rates of knee and hip surgeries.
Methods: We used healthcare data for the population of the southernmost region in Sweden (1.4 million inhabitants). We did an interrupted time-series analysis to estimate changes in rates and trends of joint replacements (JR), arthroscopies, and fracture surgeries for knee or hip in April-December 2020 compared to pre-COVID-19 levels adjusting for seasonal variations.
Results: We found a drop of 54% (95% CI 42%; 68%) and 42% (95% CI 32%; 52%), respectively, in the rate of JRs and arthroscopies in April 2020 when compared to the counterfactual scenario. This was followed by an increase that brought the rates of JRs and arthroscopies back to their predicted levels also during the beginning of the second wave (November-December 2020). Acute fracture surgeries were largely unaffected, i.e. did not show any decrease as observed for the other surgeries.
Conclusions: In southern Sweden, we observed a marked decrease in elective knee and hip surgeries following the first wave of Covid-19. The rates remained close to normal during the beginning of the second wave suggesting that important elective surgeries for patients with end-stage osteoarthritis can still be offered despite an ongoing pandemic provided adequate routines and hospital resources.

Aim: To explore whether MRI features suggestive of knee OA are associated with presence of knee pain in possible early-stage OA development.
Methods: We included 294 participants from the Osteoarthritis Initiative (mean [SD] age 50 (3) years, 50% women), with baseline Kellgren and Lawrence grade=0 in both knees, and who had all obtained knee MRIs from 4 different time points over 6 years (baseline, 24, 48 and 72 months). Using a linear mixed model (knees matched within individuals), we studied whether MRI features: meniscal body extrusion (millimeter), cartilage area loss (score 0 to 39), cartilage full thickness loss (0-16), osteophytes (0-29), meniscal integrity (0-10), bone marrow lesions (BML) including bone marrow cysts (0-20), Hoffa or effusion synovitis (absent/present) and popliteal cysts (absent/present) were associated with knee-specific pain as reported on the Knee injury and Osteoarthritis Outcomes Score (KOOS) questionnaire on 0-100 scale (worst-best).
Results: The difference in KOOS knee pain for a knee with a one unit higher score on MRI feature was: for meniscal extrusion -1.52 (95% CI -2.35,-0.69), cartilage area loss -0.23 (-0.48,0.02), cartilage full thickness loss: -1.04 (-1.58,-0.50), osteophytes -0.32 (-0.61,-0.03), meniscal integrity -0.28 (-0.58,0.02), BMLs including potential cysts -0.19 (-0.55,0.16), synovitis 0.23 (-1.14,1.60) and popliteal cysts 0.86 (-0.56,2.29).
Conclusions: Meniscal extrusion, full thickness cartilage loss and osteophytes are associated with having more knee pain. Although these features may be relevant targets for future trials, the clinical relevance of our findings is unclear because no feature was associated with a clinically important difference in knee pain.