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A loss of primary cilia by a reduction in mTOR signaling correlates with age-related deteriorations in condylar cartilage

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Abstract

Age-related deterioration of condylar cartilage is an etiological factor in temporomandibular joint-osteoarthritis (TMJ-OA). However, its underlying mechanism remains unknown. Therefore, we examined age-related changes and the relationship between mTOR signaling and primary cilia in condylar cartilage to determine the intrinsic mechanisms of age-related TMJ-OA. Age-related morphological changes were analyzed using micro-computed tomography and safranin O-stained histological samples of the mandibular condyle of C57BL/6J mice (up to 78 weeks old). Immunohistochemistry was used to assess the activity of mTOR signaling, primary cilia frequency, and Golgi size of condylar chondrocytes. Four-week-old mice receiving an 11-week series of intraperitoneal injections of rapamycin, a potent mTOR signaling inhibitor, were used for the histological evaluation of the condylar cartilage. The condylar cartilage demonstrated an age-related reduction in cartilage area, including chondrocyte size, cell density, and cell size distribution. The Golgi size, primary cilia frequency, and mTOR signaling also decreased with age. Rapamycin injections resulted in both diminished cartilage area and cell size, resembling the phenotypes observed in aged mice. Rapamycin-injected mice also exhibited a smaller Golgi size and lower primary cilia frequency in condylar cartilage. We demonstrated that a loss of primary cilia due to a decline in mTOR signaling was correlated with age-related deteriorations in condylar cartilage. Our findings provide new insights into the tissue homeostasis of condylar cartilage, contributing to understanding the etiology of age-related TMJ-OA.

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Abbreviations

TMJ:

Temporomandibular joint

OA:

Osteoarthritis

ECM:

Extracellular matrix

IFT:

Intraflagellar transport

mTOR:

Mechanistic/mammalian target of Rapamycin

pS6:

Phosphorylated ribosomal protein S6 kinase

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Funding

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JP19K19088 and JP21K17035 to MKi).

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Authors and Affiliations

  1. Division of Dental Pharmacology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

    Megumi Kitami & Lay Thant

  2. Center for Advanced Oral Science, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

    Megumi Kitami, Lay Thant & Takeyasu Maeda

  3. Division of Bio-Prosthodontics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

    Masaru Kaku

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  1. Megumi Kitami
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  4. Takeyasu Maeda
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Contributions

Conception and design: M.Ki; Conducting the experiments: M.Ki. L.T.; Analysis and interpretation of the data: M.Ki; Drafting of the article: M.Ki.; Review and editing of the article: M.Ka and T.M.

Corresponding authors

Correspondence to Megumi Kitami or Masaru Kaku.

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Ethical statement

All animal experimental protocols were approved by the Animal Care and Experimentation Committee of Niigata University (SA00959).

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No potential conflict of interest was reported by the authors.

(A) Micro-CT analysis of mouse mandibular condyle at 5, 15, 26, 52, and 78 weeks. Bar, 0.5 mm. (B) Bone mineral density (BMD) of the mandibular condyle. (C) The mandibular condyle was stained with safranin O at five, 15, 26, 52, and 78 weeks. Bar, 50 μm. (D–G) Cartilage area, safranin O-positive area, cell density, and cell size distribution were quantified in the condylar cartilage with age. Data in (B), (D), (E), and (F) are represented as mean ± SD; n = 5 in each group. aP < 0.05, vs. 5 w; AP < 0.01, vs. 5 w; bP < 0.05, vs. 15 w; BP < 0.01, vs. 15 w; cP < 0.05, vs. 26 w; CP < 0.01, vs. 26 w; DP < 0.01, vs. 52 w.

(A) Immunohistochemistry of cis-Golgi marker GM130 in condylar cartilage. Bars, 10 μm. (B) The Golgi apparatus size of chondrocytes of all layers in the condylar cartilage was quantified. (C) Age-related changes in primary cilia were examined via immunohistochemistry of the condylar cartilage using anti-acetylated tubulin and anti-gamma-tubulin antibodies. Bars, 10 μm. (D) Primary cilia frequency in chondrocytes. (E) Immunohistochemistry analysis of pS6. Bars, 10 μm. (F) The ratio of pS6-positive chondrocytes. The white square indicates the region of interest in the high-magnification image shown in (A) (C) and (E). Data in (B) (D) and (F) are represented as mean ± SD; n = 5 in each group. aP < 0.05, vs. 5 w; AP < 0.01, vs. 5 w; bP < 0.05, vs. 15 w; BP < 0.01, vs. 15 w; cP < 0.05, vs. 26 w.

(A-D) ATDC5 cells, a chondroprogenitor cell line, were treated with DMSO as control (Cont) or MHY1485. (A) Immunocytochemistry analysis using anti-acetylated tubulin, anti-gamma-tubulin, and anti-pS6. Cells were counterstained with DAPI. Bars, 10 μm. (B) Cell number. (C) The ratio of pS6-positive cells. (D) Primary cilia frequency. (E–H) ATDC5 cells were treated with ethanol as control (Cont) or Rapamycin (RAP). (E) Immunocytochemistry analysis using anti-acetylated tubulin, anti-gamma-tubulin, and anti-pS6. Cells were counterstained with DAPI. Bars, 10 μm. (F) Cell number. (G) The ratio of pS6-positive cells. (H) Primary cilia frequency. The white square indicates the region of interest in the high-magnification image shown in (A) and (E). Arrowheads indicate the primary cilia. Data in (B), (C), (D), (F), (G), and (H) are represented as mean ± SD; n = 6 in each group. *: P < 0.05, as compared to vehicle.

(A-C) Mice were injected with the vehicle as control (Cont) or rapamycin (RAP) for one week. (A) Immunohistochemistry analysis using anti-acetylated tubulin, anti-gamma-tubulin, and anti-pS6 antibodies in the condylar cartilage. Bars, 10 μm. (B) The ratio of pS6-positive cells. (C) Primary cilia frequency. (D-F) Mice were injected with a vehicle as control (Cont) or rapamycin (RAP) for 11 weeks. (D) Immunohistochemistry analysis in the condylar cartilage. Bars, 10 μm. (E) The ratio of pS6-positive cells. (F) Primary cilia frequency. The white square indicates the region of interest in the high-magnification image shown in (A) and (D). Arrowheads indicate the primary cilia. Data in (B), (C), (E), and (F) are represented as mean ± SD; n = 6 in each group. *: P < 0.05, as compared to control.

Mice were injected with a vehicle as control (Cont) or rapamycin (RAP) for 11 weeks. (A) The mandibular condylar cartilage was stained with safranin O Bars, 100 μm. (B–E) Cartilage area, safranin O-positive area, cell density, and cell size distribution of the condylar cartilage in rapamycin/vehicle-injected mice. (F) cis-Golgi marker GM130 in condylar cartilage in rapamycin/vehicle-injected mice. Bars, 10 μm. (G) Golgi apparatus size. The white square indicates the region of interest in the high-magnification image shown in (F). Data in (B), (C), (D), and (G) are represented as mean ± SD; n = 6 in each group. *: P < 0.05, as compared to control.

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Kitami, M., Kaku, M., Thant, L. et al. A loss of primary cilia by a reduction in mTOR signaling correlates with age-related deteriorations in condylar cartilage. GeroScience (2024). https://doi.org/10.1007/s11357-024-01143-x

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