Genetic mechanisms of knee osteoarthritis: a population-based longitudinal study

To describe the differences in knee structure and non-knee structural factors between offspring having at least one parent with a total knee replacement for severe primary knee osteoarthritis and age- and sex-matched controls with no family history of knee osteoarthritis, a population-based longitudinal study of 163 matched pairs (mean age 45 years, range 26 to 61) was performed at baseline and about 2 years later. Knee cartilage defect score (0 to 4), cartilage volume and bone size were determined with T1-weighted fat saturation magnetic resonance imaging. Body mass index (BMI), lower-limb muscle strength, knee pain, physical work capacity at 170 beats/minute (PWC170) and radiographic osteoarthritis were measured by standard protocols. In comparison with controls, offspring had higher annual knee cartilage loss (-3.1% versus -2.0% at medial tibial site, -1.9% versus -1.1% at lateral tibial site and -4.7% versus -3.7% at patellar site, all P < 0.05), a greater increase in medial cartilage defect score (+0.15 versus -0.01, P < 0.05) and a greater decline in PWC170 (-0.7 watts/kg versus -0.4 watts/kg, P < 0.01). There were no significant differences in change in BMI, lower-limb muscle strength, knee pain or tibial bone area between these two groups; however, the differences in knee cartilage loss and cartilage defect change decreased in magnitude and became non-significant after adjustment for baseline cartilage volume, tibial bone area, BMI and knee pain. This longitudinal study suggests that knee cartilage loss, change in cartilage defects and decrease in physical fitness all have roles in the development of knee osteoarthritis, which is most probably polygenic but may reflect a shared environment. Importantly, the cartilage changes are largely dependent on baseline differences in cartilage volume, tibial bone area, BMI and knee pain, suggesting that these factors might have a role in their initiation

Early radiographic osteoarthritis is associated with substantial changes in cartilage volume and tibial bone surface area in both males and females11Sources of support: National Health and Medical Research Council of Australia, Masonic Centenary Medical Research Foundation.

AbstractObjective: To describe the association between early radiographic osteoarthritis of the knee (ROA), knee cartilage volume and tibial bone surface area.Methods: Cross-sectional convenience sample of 372 male and female subjects (mean age 45 years, range 26–61). Articular cartilage volume, bone area and volume were determined at the patella, medial tibial and lateral tibial compartments by processing images acquired in the sagittal plane using T1-weighted fat saturation MRI. ROA was assessed with a standing semiflexed radiograph and the OARSI atlas for joint space narrowing and osteophytosis. Both radiographs and MRIs were performed in the right knee and read by different observers.Results: ROA (predominantly grade 1) was present in 17% of subjects of which medial joint space narrowing was most common (14%) followed by medial osteophytes (6%). Grade one medial joint space narrowing was associated with substantial reductions in cartilage volume at both the medial and lateral tibial and patellar sites within the knee (adjusted mean difference 11–13%, all P<0.001) while grade one osteophytosis was associated with substantial increases in both lateral and medial tibial joint surface area (adjusted mean difference 10–16%, all P<0.001). In contrast, osteophytosis was not associated with a significant change in cartilage volume and joint space narrowing was not associated with a significant change in tibial bone area (all P>0.05).Conclusions: Early medial compartment ROA is associated with substantial reductions in cartilage volume and increases in bone area. These large changes, when combined with similar measurement error for MRI and radiographs, suggest that MRI may be superior at detecting and hence understanding early osteoarthritis of the knee in humans

Familial, structural, and environmental correlates of MRI-defined bone marrow lesions: a sibpair study

The aim of this study was to estimate the heritability and describe the correlates of bone marrow lesions in knee subchondral bone. A sibpair design was used. T2- and T1-weighted MRI scans were performed on the right knee to assess bone marrow lesions at lateral tibia and femora and medial tibia and femora, as well as chondral defects. A radiograph was taken on the same knee and scored for individual features of osteoarthritis (radiographic osteoarthritis; ROA) and alignment. Other variables measured included height, weight, knee pain, and lower-limb muscle strength. Heritability was estimated with the program SOLAR (Sequential Oligogenetic Linkage Analysis Routines). A total of 115 siblings (60 females and 55 males) from 48 families, representing 95 sib pairs, took part. The adjusted heritability estimates were 53 ± 28% (mean ± SEM; p = 0.03) and 65 ± 32% (p = 0.03) for severity of bone marrow lesions at lateral and medial compartments, respectively. The estimates were reduced by 8 to 9% after adjustment for chondral defects and ROA (but not alignment). The adjusted heritability estimate was 99% for prevalent bone marrow lesions at both lateral and medial compartments. Both lateral and medial bone marrow lesions were significantly correlated with age, chondral defects, and ROA of the knee (all p < 0.05). Medial bone marrow lesions were also more common in males and were correlated with body mass index (BMI). Thus, bone marrow lesions have a significant genetic component. They commonly coexist with chondral defects and ROA but only share common genetic mechanisms to a limited degree. They are also more common with increasing age, male sex, and increasing BMI

The optimization analysis of multi-type demand-side flexibility resources for renewable energy accommodation in electrical power systems

The significant increase in the proportion of renewable energy access has led to a burgeoning and urgent demand for flexible resources within the power system, and the prominence of flexible resources on the demand side has been underscored. The existing research on demand-side response primarily focuses on addressing peak load challenges, while the optimization of demand response for accommodating renewable energy remains inadequate. Considering this issue, the present study initially examines the flexibility mechanism offered by demand-side resources and proposes a calculation approach for determining the adjustable capacity of demand-side flexible resources. Furthermore, considering the limitations of the load that can be shifted, transferred, and curtailed, we develop a collaborative optimization operational model for accommodating renewable energy with multiple types of demand response. Finally, based on the provincial power grid example, the simulation study verifies the efficacy of a multi-type demand response. The results demonstrate that shiftable and transferable loads can effectively facilitate the accommodation of new energy, and their optimal allocation capacity ratios are 5.8% and 2.3%, respectively

Knee meniscal extrusion in a largely non-osteoarthritic cohort: association with greater loss of cartilage volume

We conducted a longitudinal study (duration 2 years), including 294 individuals (mean age 45 years, 58% female), in order to examine associations between meniscal extrusion, knee structure, radiographic changes and risk factors for osteoarthritis (OA) in a largely non-osteoarthritic cohort. Meniscal extrusion, tibiofemoral cartilage defect score and cartilage volume, and tibial plateau bone area were determined using T1-weighted fat-saturated magnetic resonance imaging. At baseline the presence of medial meniscal extrusion was significantly associated with body mass index (odds ratio [OR] per kg/m2 = 1.13, 95% confidence interval [CI] = 1.02–1.25), past knee injury (positive versus negative history: OR = 3.73, 95% CI = 1.16–11.97), medial tibial bone area (OR per cm2 = 1.37, 95% CI = 1.02–1.85), and osteophytes (OR per grade = 4.89, 95% CI = 1.59–15.02). Two-year longitudinal data revealed that medial meniscal extrusion at baseline was associated with a greater rate of loss of medial tibiofemoral cartilage volume (extrusion versus no extrusion: -1.4%/year; P < 0.05) and greater risk for increased medial femoral cartilage defects (OR = 2.59, 95% CI = 1.14–5.86) and lateral tibial cartilage defects (OR = 2.64, 95% CI = 1.03–6.76). However, the latter two associations became nonsignificant after adjustment for tibial bone area and osteophytes. This study suggests that increasing body mass index and bone size, past knee injury, and osteophytes may be causally related to meniscal extrusion. Most importantly, meniscal extrusion at baseline is associated with greater loss of knee cartilage over 2 years, and this seems to be mediated mostly by subchondral bone changes, suggesting extrusion represents one pathway between bone expansion and cartilage loss

AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis

The adenosine monophosphate (AMP)–activated protein kinase (AMPK) was initially identified as an enzyme acting as an “energy sensor” in maintaining energy homeostasis via serine/threonine phosphorylation when low cellular adenosine triphosphate (ATP) level was sensed. AMPK participates in catabolic and anabolic processes at the molecular and cellular levels and is involved in appetite-regulating circuit in the hypothalamus. AMPK signaling also modulates energy metabolism in organs such as adipose tissue, brain, muscle, and heart, which are highly dependent on energy consumption via adjusting the AMP/ADP:ATP ratio. In clinics, biguanides and thiazolidinediones are prescribed to patients with metabolic disorders through activating AMPK signaling and inhibiting complex I in the mitochondria, leading to a reduction in mitochondrial respiration and elevated ATP production. The role of AMPK in mediating skeletal development and related diseases remains obscure. In this review, in addition to discuss the emerging advances of AMPK studies in energy control, we will also illustrate current discoveries of AMPK in chondrocyte homeostasis, osteoarthritis (OA) development, and the signaling interaction of AMPK with other pathways, such as mTOR (mechanistic target of rapamycin), Wnt, and NF-κB (nuclear factor κB) under OA condition

Effect of Vitamin D Supplementation on Aortic Stiffness and Arterial Hemodynamics in People With Osteoarthritis and Vitamin D Deficiency

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Characterization Of Induced Neural Progenitors From Skin Fibroblasts By A Novel Combination Of Defined Factors

Recent reports have demonstrated that somatic cells can be directly converted to other differentiated cell types through ectopic expression of sets of transcription factors, directly avoiding the transition through a pluripotent state. Our previous experiments generated induced neural progenitor-like cells (iNPCs) by a novel combination of five transcription factors (Sox2, Brn2, TLX, Bmi1 and c-Myc). Here we demonstrated that the iNPCs not only possess NPC-specific marker genes, but also have qualities of primary brain-derived NPCs (WT-NPCs), including tripotent differentiation potential, mature neuron differentiation capability and synapse formation. Importantly, the mature neurons derived from iNPCs exhibit significant physiological properties, such as potassium channel activity and generation of action potential-like spikes. These results suggest that directly reprogrammed iNPCs closely resemble WT-NPCs, which may suggest an alternative strategy to overcome the restricted proliferative and lineage potential of induced neurons (iNCs) and broaden applications of cell therapy in the treatment of neurodegenerative disorders