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. 2022 Sep 23;23(19):11237.
doi: 10.3390/ijms231911237.

Increased NMUR1 Expression in Mast Cells in the Synovial Membrane of Obese Osteoarthritis Patients

Ayumi Tsukada  1 , Ken Takata  1 , Shotaro Takano  1 , Yoshihisa Ohashi  1 , Manabu Mukai  1 , Jun Aikawa  1 , Dai Iwase  1 , Gen Inoue  1 , Masashi Takaso  1 , Kentaro Uchida  1   2
Affiliations

Increased NMUR1 Expression in Mast Cells in the Synovial Membrane of Obese Osteoarthritis Patients

Ayumi Tsukada et al. Int J Mol Sci. .

Abstract

Obesity is a risk factor for knee osteoarthritis (KOA). Neuromedin U (NMU) and NMU receptors (NMUR1 and NMUR2) are associated with obesity-related disorders and found in mast cells (MCs), which are elevated in osteoarthritis. However, NMU/NMUR expression was not examined in the synovial membrane (SM) or synovial MCs of obese osteoarthritis patients. We compared expression of NMU, NMUR1, NMUR2, and the mast cell (MC) marker, CPA3, in the SM of KOA patients categorized as normal weight (NW; BMI < 25 kg/m2, n = 79), overweight (OW; BMI ≥ 25 and <30 kg/m2, n = 87), and obese (OB; ≥30 kg/m2, n = 40). To study NMU/NMUR expression in MCs, we compared the MC-rich fraction (MC-RF), CD88(+) MC-RF, and CD88(−) MC-RF, extracted using magnetic isolation, with the MC-poor fraction (MC-PF). While NMU and NMUR2 expression were comparable, NMUR1 was significantly elevated in OW and OB compared to NW. Moreover, CPA3 levels were significantly greater in OB than NW. NMUR1 and CPA3 expression were significantly higher in both the CD88(+) and CD88(−) MC-RF than MC-PF. Therefore, NMUR1 expression was elevated in the SM of OB KOA patients, and its expression was found in MCs. Further investigation to analyze the NMU/NMUR1 pathway in MC may provide a link between obesity and KOA pathology.

Keywords: mast cells; neuromedin; neuromedin receptors; obese; osteoarthritis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Expression of CPA3 and NMU/NMURs in the synovial membrane of normal-weight, overweight, and obese groups. The expression of NMU/NMURs and CPA3 mRNA in NW, OW, and OB groups was estimated by qPCR (A–D). NMU (A), NMUR1 (B), NMUR2 (C), and CPA3 (D) mRNA expression in the synovial membrane of normal-weight (NW, n = 79), overweight (OW, n = 87), and obese (OB, n = 40) patients with knee osteoarthritis. Gene expression is presented in box and whisker plots, showing the median, 25th, and 75th percentiles and range. * p < 0.05.
Figure 2
Figure 2
Expression of NMU/NMURs and CPA3 in normal-weight and obese groups after propensity score matching. The expression of NMU/NMURs and CPA3 mRNA in normal-weight (NW, n = 38) and obese (OB, n = 38) groups in a propensity score-matched cohort was estimated by qPCR (A–D). The expression of NMU (A), NMUR1 (B), NMUR2 (C), CPA3 (D) mRNA in the synovial membrane of NW and OB patients with knee osteoarthritis after propensity score matching. Gene expressions are presented in box and whisker plots, showing the median, 25th, and 75th percentiles and range. * p < 0.05.
Figure 3
Figure 3
Expression of NMU/NMURs and CPA3. (A) Schematic showing the process used to isolate the mast cell (MC)-poor fraction (MC-PF; THY-1+, CD3+, CD14+, or CD19+CD235+) and CD88(−) and CD88(+) MC-rich fractions (MC-RFs; THY-1-CD3-CD14-CD19-CD235-). MC-RF and MC-PF were magnetically separated from other synovium-derived cells using biotin-conjugated antibody cocktails and streptavidin beads. Subsequently, the MC-RF was further divided into CD88(−) and CD88(+) MC-RFs using PE-conjugated anti-CD88 antibody and anti-PE beads. The expression of NMU/NMURs and CPA3 mRNA in non-MC and CD88(−) and CD88(+) MC fractions was estimated by qPCR (B–F). CD88 (B), NMU (C), NMUR1 (D), NMUR2(E), and CPA3 (F) expression levels in MC-PF and CD88(−) and CD88(+) MC-RF derived from the synovial membrane of obese KOA patients (n = 5). * p < 0.05.
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