Temporomandibular joint osteoarthritis (TMJOA) is a complex inflammatory condition with multiple factors and degenerative processes co-occurring. However, its pathogenesis remains uncertain. The purpose of the study was to observe the expression of Indian hedgehog (Ihh) signal related molecules in TMJOA induced by bite-raising and to study the effect and mechanism of Ihh signaling. Our research indicated that Ihh signaling pathway can be activated in condylar cartilage induced by bite-raising. The histological analysis showed TMJOA-like structural changes of condylar cartilage in experiment groups. Ihh, Smoothened (Smo), and Gli zinc finger transcription factors-1 (Gli-1) were activated in the experimental groups, and the expression levels increased significantly over time, whereas the sham control groups showed no fluctuation. Additionally, the expression levels of matrix metalloproteinase-13 (MMP-13) and cysteinyl aspartate specific proteinase-3 (Caspase-3) in the experiment groups increased in a time-dependent manner compared with the matched sham control groups. In conclusion, our results indicated that the Ihh signaling pathway may activate the occurrence of TMJOA by mediating the hypertrophy of chondrocytes, which may be an important regulatory mechanism and potential therapeutic target in the repair of condylar cartilage.
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Abramson SB, Attur M, Yazici Y (2006) Prospects for disease modification in osteoarthritis. Nat Clin Pract Rheumatol 2:304–312. https://doi.org/10.1038/ncprheum0193
Al Faqeh H, Nor Hamdan BM, Chen HC, Aminuddin BS, Ruszymah BH (2012) The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol 47:458–464. https://doi.org/10.1016/j.exger.2012.03.018
Amano K, Densmore M, Nishimura R, Lanske B (2014) Indian hedgehog signaling regulates transcription and expression of collagen type X via Runx2/Smads interactions*. J Biol Chem 289:24898–24910. https://doi.org/10.1074/jbc.m114.570507
Boehme KA, Rolauffs B (2018) Onset and progression of human osteoarthritis—can growth factors, inflammatory cytokines, or differential miRNA expression concomitantly induce proliferation, ECM degradation, and inflammation in articular cartilage? Int J Mol Sci. https://doi.org/10.3390/ijms19082282
Chen CG, Thuillier D, Chin EN, Alliston T (2012) Chondrocyte-intrinsic Smad3 represses Runx2-inducible MMP-13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheumatol 64:3278–3289. https://doi.org/10.1002/art.34566
Chen S, Fu P, Wu H, Pei M (2017) Meniscus, articular cartilage and nucleus pulposus: a comparative review of cartilage-like tissues in anatomy, development and function. Cell Tissue Res 370:53–70. https://doi.org/10.1007/s00441-017-2613-0
Goldring MB, Goldring SR (2010) Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann NY Acad Sci 1192:230–237. https://doi.org/10.1111/j.1749-6632.2009.05240.x
Kang DG, Lee HJ, Lee CJ, Park JS (2018) Inhibition of the expression of matrix metalloproteinases in articular chondrocytes by resveratrol through affecting nuclear factor-kappa B signaling pathway. Biomol Ther (Seoul) 26:560–567. https://doi.org/10.4062/biomolther.2018.132
Kurio N et al (2018) Roles of Ihh signaling in chondroprogenitor function in postnatal condylar cartilage. Matrix Biol 67:15–31. https://doi.org/10.1016/j.matbio.2018.02.011
Kuroda S, Tanimoto K, Izawa T, Fujihara S, Koolstra JH, Tanaka E (2009) Biomechanical and biochemical characteristics of the mandibular condylar cartilage. Osteoarthr Cartil 17:1408–1415. https://doi.org/10.1016/j.joca.2009.04.025
Lin AC et al (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15:1421. https://doi.org/10.1038/nm.2055
Liu Y, Lin L, Zou R, Wen C, Wang Z, Lin F (2018) MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis. Cell Cycle 17:2411–2422. https://doi.org/10.1080/15384101.2018.1526603
Mackie EJ, Tatarczuch L, Mirams M (2011) The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. J Endocrinol 211:109–121. https://doi.org/10.1530/joe-11-0048
Maeda Y, Schipani E, Densmore MJ, Lanske B (2010) Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor. Bone 46:472–478. https://doi.org/10.1016/j.bone.2009.09.009
Makiguchi M et al (2016) Effects of increased occlusal vertical dimension on the jaw-opening reflex in adult rats. Arch Oral Biol 72:39–46. https://doi.org/10.1016/j.archoralbio.2016.08.009
Mongini F (1980) Condylar remodeling after occlusal therapy. J Prosthet Dent 43:568–577
Moody HR, Heard BJ, Frank CB, Shrive NG, Oloyede AO (2012) Investigating the potential value of individual parameters of histological grading systems in a sheep model of cartilage damage: the Modified Mankin method. J Anat 221:47–54. https://doi.org/10.1111/j.1469-7580.2012.01513.x
Naito S, Ishida T, Kokai S, Fujita K, Shibata M, Yabushita T, Ono T (2011) Functional adaptability of temporomandibular joint mechanoreceptors after an increase in the occlusal vertical dimension in rats. Angle Orthod 81:453–459. https://doi.org/10.2319/082010-489.1
Ng TC, Chiu KW, Rabie AB, Hagg U (2006) Repeated mechanical loading enhances the expression of Indian hedgehog in condylar cartilage. Front Biosci 11:943–948
Nurminskaya M, Linsenmayer TF (1996) Identification and characterization of up-regulated genes during chondrocyte hypertrophy. Dev Dyn 206:260–271. https://doi.org/10.1002/(sici)1097-0177(199607)206:3%3c260:aid-aja4%3e3.0.co;2-g
Ohashi N, Robling AG, Burr DB, Turner CH (2002) The effects of dynamic axial loading on the rat growth plate. J Bone Miner Res 17:284–292. https://doi.org/10.1359/jbmr.2002.17.2.284
Pan A, Chang L, Nguyen A, James AW (2013) A review of hedgehog signaling in cranial bone development. Front Physiol. https://doi.org/10.3389/fphys.2013.00061
Pathi S, Rutenberg JB, Johnson RL, Vortkamp A (1999) Interaction of Ihh and BMP/Noggin signaling during cartilage differentiation. Dev Biol 209:239–253. https://doi.org/10.1006/dbio.1998.9181
Rolfe RA et al (2014) Identification of mechanosensitive genes during skeletal development: alteration of genes associated with cytoskeletal rearrangement and cell signalling pathways. BMC Genomics 15:48. https://doi.org/10.1186/1471-2164-15-48
Rose BJ, Kooyman DL (2016) A tale of two joints: the role of matrix metalloproteases in cartilage biology. Dis Markers 2016:4895050. https://doi.org/10.1155/2016/4895050
Sabol M, Trnski D, Musani V, Ozretić P, Levanat S (2018) Role of GLI transcription factors in pathogenesis and their potential as new therapeutic targets. Int J Mol Sci. https://doi.org/10.3390/ijms19092562
Tanaka E, Aoyama J, Miyauchi M, Takata T, Hanaoka K, Iwabe T, Tanne K (2005) Vascular endothelial growth factor plays an important autocrine/paracrine role in the progression of osteoarthritis. Histochem Cell Biol 123:275–281. https://doi.org/10.1007/s00418-005-0773-6
Tanaka E, Detamore MS, Mercuri LG (2008) Degenerative disorders of the temporomandibular joint: etiology, diagnosis, and treatment. J Dent Res 87:296–307. https://doi.org/10.1177/154405910808700406
Tang GH, Rabie AB, Hagg U (2004) Indian hedgehog: a mechanotransduction mediator in condylar cartilage. J Dent Res 83:434–438. https://doi.org/10.1177/154405910408300516
Tchetina EV, Markova GA (2018) Regulation of energy metabolism in the growth plate and osteoarthritic chondrocytes. Rheumatol Int 38:1963–1974. https://doi.org/10.1007/s00296-018-4103-4
van der Kraan PM, van den Berg WB (2012) Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration? Osteoarthr Cartil 20:223–232. https://doi.org/10.1016/j.joca.2011.12.003
Wang XD, Zhang JN, Gan YH, Zhou YH (2015) Current understanding of pathogenesis and treatment of TMJ osteoarthritis. J Dent Res 94:666–673. https://doi.org/10.1177/0022034515574770
Wei F et al (2012) Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage. Osteoarthr Cartil 20:755–763. https://doi.org/10.1016/j.joca.2012.03.010
Wong M, Siegrist M, Goodwin K (2003) Cyclic tensile strain and cyclic hydrostatic pressure differentially regulate expression of hypertrophic markers in primary chondrocytes. Bone 33:685–693
Xia B, Di C, Zhang J, Hu S, Jin H, Tong P (2014) Osteoarthritis pathogenesis: a review of molecular mechanisms. Calcif Tissue Int 95:495–505. https://doi.org/10.1007/s00223-014-9917-9
Yu J et al (2019) MMP-3 and MMP-8 in rat mandibular condylar cartilage associated with dietary loading, estrogen level, and aging. Arch Oral Biol 97:238–244. https://doi.org/10.1016/j.archoralbio.2018.10.037
Zhang C et al (2014) Indian hedgehog in synovial fluid is a novel marker for early cartilage lesions in human knee joint. Int J Mol Sci 15:7250–7265. https://doi.org/10.3390/ijms15057250
Zhou J et al (2014) Disrupting the Indian hedgehog signaling pathway in vivo attenuates surgically induced osteoarthritis progression in Col2a1-CreERT2; Ihhfl/fl mice. Arthritis Res Ther 16:R11. https://doi.org/10.1186/ar4437
This Project was supported by the Provincial Key Research and Development Project of Shanxi Province (Grant Number 201803D31065).
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Long, Hq., Tian, Pf., Guan, Yx. et al. Expression of Ihh signaling pathway in condylar cartilage after bite-raising in adult rats. J Mol Hist 50, 459–470 (2019). https://doi.org/10.1007/s10735-019-09840-0
- Condylar cartilage
- Ihh signal related molecules