Alpha-7 Nicotinic Receptor Dampens Murine Osteoblastic Response to Inflammation and Age-Related Osteoarthritis.

Introduction: Osteoarthritis (OA) is a whole-joint disease characterized by a low-grade inflammation that is involved in both cartilage degradation and subchondral bone remodeling. Since subchondral bone has a cholinergic innervation and that acetylcholine (Ach) might have an anti-inflammatory effect through the α7 nicotinic Ach receptor (α7nAchR), we aimed (i) to determine the expression of non-neuronal cholinergic system and nicotinic receptor subunits by murine and human osteoblasts, (ii) to address the role of α7nAchR in osteoblastic response to inflammation, and (iii) to study the role of α7nAchR in a spontaneous aging OA model. Methods: Primary cultures of WT and α7nAchR knock-out mice (Chrna7-/-) murine osteoblasts and of subchondral bone human OA osteoblasts were performed. The expressions of the non-neuronal cholinergic system and of the nAchR subunits were assessed by PCR. In vitro, IL1ß-stimulated WT, Chrna7-/-, and human osteoblasts were pretreated with nicotine. At 24 h, expressions of interleukin-6 (IL6) and metalloproteinase-3 and -13 (MMP), RANK-ligand (RANKL), and osteoprotegerin (OPG) were quantified by qPCR and ELISA. Spontaneous aging OA was evaluated and compared between male WT and Chrna7-/- mice of 9 and 12 months. Results: Murine WT osteoblasts express the main components of the cholinergic system and α7 subunit composing α7nAchR. Nicotine partially prevented the IL1ß-induced expression and production of IL6, MMP3, and RANKL in WT osteoblasts. The effect for IL6 and MMP was mediated by α7nAchR since nicotine had no effect on Chrna7-/- osteoblasts while the RANKL decrease persisted. Chrna7-/- mice displayed significantly higher cartilage lesions than their WT counterparts at 9 and 12 months, without difference in subchondral bone remodeling. Human OA osteoblasts also expressed the non-neuronal cholinergic system and α7 subunit as well as CHRFAM7A, the dominant negative duplicate of Chrna7. Nicotine pretreatment did not significantly reduce IL6 and MMP3 production in IL-1ß-stimulated human osteoarthritic osteoblasts (n = 4), possibly due to CHRFAM7A. Conclusion: Cholinergic system counteracts murine osteoblastic response to IL-1ß through α7nAchR. Since α7nAchR deletion may limit cartilage degradation during murine age-related OA, enhancing cholinergic system could be a new therapeutic target in OA but may depend on CHRFAM7A expression.

Metacarpophalangeal Joint Impairment in Hand Osteoarthritis and Its Association With Mechanical Factors: Results From the Digital Cohort Osteoarthritis Design Hand Osteoarthritis Cohort.

OBJECTIVE: To determine the prevalence, distribution, and characteristics associated with radiographic metacarpophalangeal (MCP) joint osteoarthritis (OA). METHODS: This was a cross-sectional study of baseline data from the Digital Cohort Osteoarthritis Design, a French monocentric cohort including patients with symptomatic hand OA. We evaluated the prevalence of radiographic MCP joint OA, defined as ≥2 MCP joints with a Kellgren/Lawrence score of ≥2. We compared the prevalence of MCP joint OA in the dominant and nondominant hands. Associations between radiographic MCP joint OA and patient characteristics were studied using univariable and multivariable logistic regression. RESULTS: Radiographic MCP joint OA was present in 138 of the 425 patients (32.5%) but was not severe. Patients with MCP joint OA had a mean age of 69.2 ± 6.9 years, a body mass index of 25 ± 4.2 kg/m2 , and 86.2% were women. MCP joint OA was more frequent in the dominant hand and predominated at the first and second MCP joints. In the multivariable analysis, MCP joint OA was associated with older age (odds ratio [OR] 1.05 [95% confidence interval (95% CI) 1.01, 1.10] for each year), manual occupation (OR 3.74 [95% CI 1.21, 11.54]), scaphotrapezial OA (OR 2.18 [95% CI 1.27, 3.72]), and a high number of proximal interphalangeal joints with radiographic OA. MCP joint OA was not associated with metabolic syndrome or hand OA symptoms. CONCLUSION: In this cross-sectional study using a hospital-based hand OA cohort, radiographic MCP joint OA was frequent and associated with structural hand OA features rather than with symptom severity. Our results suggest that the involvement of MCP joints in hand OA is predominantly related to mechanical rather than systemic factors in this population.

Coagulation disorders during treatment with cefazolin and rifampicin: rare but dangerous.

We describe a 79-year-old man with spondylodiscitis and unknown pathogen, treated with cefazolin and rifampicin. He developed a massive digestive hemorrhage. Prothrombin time was prolonged with severe vitamin-K-dependent clotting-factor deficiency. Severe bleeding can occur during cefazolin and rifampicin use. This deficiency should be assessed before prescribing cefazolin-rifampicin and prothrombin time monitored.