Context: IL-1, IL-6, and TNF-α play an important role in the pathogenesis of osteoporosis in animals; however, evidence that these play a similar role in bone loss in human studies is limited.
...Objective: Our objective was to determine the associations between serum markers of inflammation and changes in bone mineral density (BMD) and urinary pyridinoline (PYR) to creatinine (Cr) ratio over 2.9 yr in older adults.
Methods: A total of 168 randomly selected subjects (mean 63 yr, range 52–78, 48% female) was studied. BMD was measured by dual-energy x-ray absorptiometry at baseline (mean T score: −0.18 to −0.61) and 2.9 yr later. Serum high-sensitivity (hs) C-reactive protein (CRP), IL-6, TNF-α, and the urinary PYR/Cr ratio were measured on both occasions.
Results: The mean annual loss of BMD was 0.15, 0.15, and 0.34% at total body, spine, and hip, respectively. Change in total body BMD was associated with baseline hs-CRP, IL-6, and TNF-α, as well as change in hs-CRP (β: −0.41%/U, 95% confidence interval −0.68%, −0.15%) and IL-6 (β: −0.62%/U, 95% confidence interval −1.01%, −0.23%). If these markers were put in the same predictive model, only IL-6 remained largely unchanged. Changes in other BMD sites were significantly predicted by IL-6 (hip and spine) and TNF-α (spine only). Finally, change in the PYR/Cr ratio was positively associated baseline IL-6, hs-CRP, and their changes (all P < 0.05) in women, but not men.
Conclusions: Variation within the low levels of inflammatory markers observed in this study, especially IL-6, predicts bone loss and resorption, suggesting that targeted antiinflammatory therapy has potential for the prevention of osteoporosis.
There is emerging evidence that the development and progression of osteoarthritis (OA) is associated with inflammation. C reactive protein (CRP), a systemic marker for inflammation, may be elevated ...in OA patients but the evidence is conflicting.
To systematically review the literature for the relationship between serum CRP levels measured by a high sensitivity method (high sensitive CRP (hs-CRP)) and OA, as well as the correlation between circulating CRP levels and OA phenotypes.
MEDLINE, EMBASE and CINAHL databases were systematically searched from January 1992 to December 2012. Studies were included when they met the inclusion criteria and data from studies were extracted. Two independent reviewers assessed study quality using a modified Newcastle-Ottawa Quality Assessment Scale. Meta-analyses were performed to pool available data from included studies.
32 studies met the inclusion criteria. Serum hs-CRP levels in OA were modestly but statistically significantly higher than controls (mean difference=1.19 mg/L, 95% CI 0.64 to 1.73, p<0.001) with significant heterogeneity between studies. Levels were significantly associated with pain (r=0.14, 95% CI 0.09 to 0.20, p<0.001) and decreased physical function (r=0.25, 95% CI 0.13 to 0.39, p<0.001). No significant associations were found between hs-CRP levels and radiographic OA.
Low-grade systemic inflammation may play a greater role in symptoms rather than radiographic changes in OA.
Osteoarthritis (OA) is the leading cause of function loss and disability among the elderly, with significant burden on the individual and society. It is a severe disease for its high disability ...rates, morbidity, costs, and increased mortality. Multifactorial etiologies contribute to the occurrence and development of OA. The heterogeneous condition poses a challenge for the development of effective treatment for OA; however, emerging treatments are promising to bring benefits for OA management in the future. This narrative review will discuss recent developments of agents for the treatment of OA, including potential disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics for pain relief. This review will focus more on drugs that have been in clinical trials, as well as attractive drugs with potential applications in preclinical research. In the past few years, it has been realized that a complex interaction of multifactorial mechanisms is involved in the pathophysiology of OA. The authors believe there is no miracle therapeutic strategy fitting for all patients. OA phenotyping would be helpful for therapy selection. A variety of potential therapeutics targeting inflammation mechanisms, cellular senescence, cartilage metabolism, subchondral bone remodeling, and the peripheral nociceptive pathways are expected to reshape the landscape of OA treatment over the next few years. Precise randomized controlled trials (RCTs) are expected to identify the safety and efficacy of novel therapies targeting specific mechanisms in OA patients with specific phenotypes.
To determine the association between inflammatory markers and change in knee pain over 5 years.
A total of 149 randomly selected subjects (mean 63 years, range 52-78; 46% female) was studied. Serum ...levels of high sensitivity C-reactive protein (hs-CRP), tumour necrosis factor alpha (TNF-α) and interleukin (IL)-6 were measured at baseline and 2.7 years later. Knee pain was recorded using the Western Ontario and McMasters osteoarthritis index questionnaire at baseline and 5 years later. Knee radiographic osteoarthritis of both knees was assessed at baseline, and knee bone marrow lesions, joint effusion and cartilage defects were determined using T1 or T2-weighted fat saturated MRI.
After adjustment for confounding variables, baseline hs-CRP was positively associated with change in total knee pain (β=0.33 per mg/l, p=0.032), as well as change in the pain at night in bed (β=0.12 per ml/pg, p=0.010) and while sitting/lying (β=0.12 per ml/pg, p=0.002). Change in hs-CRP was also associated with change in knee pain at night and when sitting/lying (both p<0.05). Baseline TNFα and IL-6 were associated with change in pain while standing (β=0.06 per ml/pg, p=0.033; β=0.16 per ml/pg, p=0.035, respectively), and change in TNFα was positively associated with change in total knee pain (β=0.66 ml/pg, p=0.020) and change in pain while standing (β=0.26 ml/pg, p=0.002). Adjustment for radiographic osteoarthritis or MRI-detected structural abnormalities led to no or minor attenuation of these associations.
Systemic inflammation is an independent predictor of worsening knee pain over 5 years.
There were overlaps between the article recently published in this journal 1 and the previous publications from the authors’ group 2-4 that they did not cite.
Osteoarthritis (OA), a disease with whole-joint damage and dysfunction, is the leading cause of disability worldwide. The progressive loss of hyaline cartilage extracellular matrix (ECM) is ...considered as its hallmark, but its exact pathogenesis needs to be further clarified. MicroRNA(miRNA) contributes to OA pathology and may help to identify novel biomarkers and therapies against OA. Here we identified miR-214–3p as an important regulator of OA.
qRT-PCR and in situ hybridization were used to detect the expression level of miR-214–3p. The function of miR-214–3p in OA, as well as the interaction between miR-214–3p and its downstream mRNA target (IKBKB), was evaluated by western blotting, immunofluorescence, qRT-PCR and luciferase assay. Mice models were introduced to examine the function and mechanism of miR-214–3p in OA in vivo.
In our study, we found that miR-214–3p, while being down-regulated in inflamed chondrocytes and OA cartilage, regulated ECM metabolism and cell apoptosis in the cartilage. Mechanically, the protective effect of miR-214–3p downregulated the IKK-β expression and led to the dysfunction of NF-κB signaling pathway. Furthermore, intra-articular injection of miR-214–3p antagomir in mice joints triggered spontaneous cartilage loss while miRNA-214–3p agomir alleviated OA in the experimental mouse models.
Decreased miR-214–3p activates the NF-κB signaling pathway and aggravates OA development through targeting IKKβ, suggesting miR-214–3p may be a novel therapeutic target for OA.
This study was financially supported by grants from the National Natural Science Foundation of China (81,773,532, 81,974,342).
The infrapatellar fat pad (IPFP) is of uncertain significance for knee osteoarthritis. The aim of this study was to describe the longitudinal associations between baseline IPFP maximal area and ...changes in knee pain, knee cartilage volume and cartilage defects in older adults.
356 community-dwelling male and female adults aged 50-80 years were measured at baseline and approximately 2.6 years later. T1-weighted or T2-weighted fat-suppressed MRI was used to assess maximal IPFP area, cartilage volume and cartilage defects at baseline and/or follow-up. Knee pain was assessed by the self-administered Western Ontario McMaster Osteoarthritis Index questionnaire.
After adjustment for confounders, IPFP maximal area in women was significantly and negatively associated with changes in knee pain (β: -0.18 to -0.86 for total knee pain, pain at night while in bed, pain when sitting/lying and pain when standing upright, all p<0.05) but not with other knee pain subscales. IPFP maximal area in women was beneficially associated with change in tibial cartilage volume per annum (β: +1.56% per cm(2) at medial site; +0.86% per cm(2) at lateral site, both p<0.05), but not with change in patellar cartilage volume. Further, it was significantly associated with reduced risks of increases in medial cartilage defects (relative risk: 0·46 at tibial site, relative risk: 0.59 at femoral site; both p<0.05) but not with increases at other sites in women. No significant associations were found in men.
While the associations are not fully consistent, IPFP maximal area appears to have a protective role for knee symptoms and cartilage damage in older female adults.
Inflammatory cytokines-induced activation of the nuclear factor κB (NF-κB) pathway plays a critical role in the pathogenesis of osteoarthritis (OA). Circular RNA (circRNA) has been identified as ...important epigenetic factor in numerous diseases. However, the biological roles of inflammation-related circRNAs in regulating OA pathogenesis remain elusive. Here, we revealed circRNA expression profiles in human primary chondrocytes with interleukin-1β (IL-1β) stimulation by circRNA sequencing. We identified a highly upregulated circRNA, termed as circNFKB1 in inflamed chondrocytes and osteoarthritic cartilage. As a circRNA derived from exon 2-5 of NFKB1, circNFKB1 is located in both cytoplasm and nucleus of chondrocytes. Furthermore, knockdown of circNFKB1 inhibited extracellular matrix (ECM) catabolism and rescued IL-1β impaired ECM anabolism whereas ectopic expression of circNFKB1 significantly promoted chondrocytes degradation in vitro. Moreover, intraarticular injection of adenovirus-circNFKB1 in mouse joints triggered spontaneous cartilage loss and OA development. Mechanistically, circNFKB1 interacted with α-enolase (ENO1), regulated the expression of its parental gene NFKB1 and sustained the activation of NF-κB signaling pathway in chondrocytes. Therefore, this study highlights a novel ENO1-interacting circNFKB1 in OA pathogenesis, and provides valuable insights into understanding the regulatory mechanism of NF-κB signaling in chondrocytes and a promising therapeutic target for the treatment of OA.
Vitamin D deficiency is a globally common situation and closely related with many chronic diseases. It is a hot topic to examine if vitamin D supplementation is effective for the treatment of ...diseases, and there have been dozens of clinical trials published in recent years. However, most studies have not proved the extra‐skeletal benefits of vitamin D supplementation on these diseases. Some inherent shortcomings of these trials, such as inclusion with vitamin D‐sufficient and obese participants, low response rate from participants and the insensitive changes in chosen outcomes over a shorter period, may be main reasons why most studies have yet to demonstrate effects of vitamin D supplementation. In this editorial, we aim to discuss the perspectives on how can we design a proper trial for vitamin D treatment of diseases based on the evidence‐based practice framework PICOS (participants, intervention, control, outcomes and study design) in the future. First, right participants should be chosen, which is crucial for the success of vitamin D clinical trials. Participants with vitamin D sufficiency (e.g., baseline 25(OH)D of >50 nmol/L), obesity (e.g., body mass index > 30 kg/m2) and/or high vitamin D response index could be excluded from the trials. Second, intervention with vitamin D in right forms or dosages should be used. Vitamin D3 supplementation with appropriate dosages that keep 25(OH)D levels between 75 and 100 nmol/L is recommended. Third, ‘contamination’ in the control groups needs to pay attention. To diminish this, it is ideal to include participants less interfered by sun exposure (such as living in places at a high latitude) or with greater compliance (less interference by supplemental vitamin D‐containing nutrients). Fourth, the outcome measures should be sensitive to change to avoid type II error. For outcomes such as bone density, radiographic osteoarthritis and cardiovascular diseases, follow‐up period of 3–5 years may be required to observe the changes. Last, precision clinical trials may be the only way to prove the benefits of vitamin D supplementation.
Summary
Objective Low 25‐hydroxyvitamin D (25OHD) levels may be associated with both sarcopenia (the age‐related decline in muscle mass and function) and low physical activity (PA). Our objective ...was to describe prospective associations between 25OHD, muscle parameters, and PA in community‐dwelling older adults.
Design Prospective, population‐based study with a mean follow‐up of 2·6 ± 0·4 years.
Patients Six hundred and eighty‐six community‐dwelling older adults (49% women; mean ± SD 62 ± 7 years old).
Measurements Appendicular lean mass percentage (%ALM) and body fat assessed by Dual‐energy X‐ray Absorptiometry, leg strength by dynamometer, leg muscle quality (LMQ), PA assessed by pedometer, self‐reported sun exposure by questionnaire, and serum 25OHD measured by radioimmunoassay.
Results Participants with 25OHD ≤50 nm had lower mean %ALM, leg strength, LMQ and PA (all P < 0·05). As a continuous function, baseline 25OHD was a positive independent predictor of change in leg strength (β = 5·74 kg, 95% CI 0·65, 10·82) and LMQ (β = 0·49 kg/kg, 95% CI 0·17, 0·82). Also, change in 25OHD was positively predicted by baseline %ALM (β = 2·03 pm/p.a., 95% CI 0·44, 3·62) leg strength (β = 0·30 pm/p.a., 95% CI 0·06, 0·53), LMQ (β = 4·48 pm/p.a., 95% CI 0·36, 8·61) and PA (β = 2·63 pm/p.a., 95% CI 0·35, 4·92) after adjustment for sun exposure and body fat.
Conclusions 25OHD may be important for the maintenance of muscle function, and higher skeletal muscle mass and function as well as general PA levels may also be beneficial for 25OHD status, in community‐dwelling older adults.
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