Calcified Tissue International

, Volume 104, Issue 4, pp 461–474 | Cite as

OPG is Required for the Postnatal Maintenance of Condylar Cartilage

  • Danying ChenEmail author
  • Yi Liu
  • Zongxiang Liu
  • Penglai Wang
Original Research


Osteoprotegerin (OPG) is one of the protective factors of bony tissue. However, the function of OPG in cartilage tissues remains elusive. The aim of this study is to explore the function of OPG in the postnatal maintenance and the occurring of osteoarthritis (OA) of temporomandibular joint (TMJ) in the rodent models. We found that OPG expressed in the hypertrophic layer of the condylar cartilage and upregulated in the hyperocclusion-induced-TMJ-trauma rat. In the absence of OPG, the cartilage degradation occurred prior to that in WT mice, and the 3-month-old OPG-Knockout (OPG-KO) condyle showed decreased chondrocyte proliferation and increased chondrocyte apoptosis, whereas the number of chondroclasts was comparable to WT condyle. The isolated chondrocytes from the OPG-KO mice also showed impaired survival and promoted chondrogenic differentiation. Furthermore, the hyperocclusion model deteriorated TMJ degradation in the OPG-KO mice. OPG plays a protective role in the condylar chondrocytes’ survival, and it is required for the postnatal maintenance of TMJ.


Osteoarthritis Temporomandibular joint Osteoprotegerin Chondrocyte Apoptosis 



We wish to thank Haiming Du and Yunfei Wang for their assistance in animal handling. This study was funded by the National Natural Science Foundation of China.

Author Contributions

DC conceived and designed the study, collected, assembled and interpreted the data, wrote the manuscript. YL collected the data, provided technical supports. ZL and PW provided technical supports. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.

Compliance with Ethical Standards

Conflict of interest

Danying Chen, Yi Liu, Zongxiang Liu, and Penglai Wang declare that they have no competing interests.

Human and Animal Rights and Informed Consent

Not applicable, as there were no human subjects. All animal protocols were approved by the Animal Use and Care Committee of Tongji University.


  1. 1.
    Liu F, Steinkeler A (2013) Epidemiology, diagnosis, and treatment of temporomandibular disorders. Dent Clin North Am 57(3):465–479. Google Scholar
  2. 2.
    Wang XD, Zhang JN, Gan YH, Zhou YH (2015) Current understanding of pathogenesis and treatment of TMJ osteoarthritis. J Dent Res 94(5):666–673. Google Scholar
  3. 3.
    Schmitter M, Essig M, Seneadza V, Balke Z, Schroder J, Rammelsberg P (2010) Prevalence of clinical and radiographic signs of osteoarthrosis of the temporomandibular joint in an older persons community. Dentomaxillofac Radiol 39(4):231–234. Google Scholar
  4. 4.
    Zhao YP, Zhang ZY, Wu YT, Zhang WL, Ma XC (2011) Investigation of the clinical and radiographic features of osteoarthrosis of the temporomandibular joints in adolescents and young adults. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111(2):e27–e34. Google Scholar
  5. 5.
    Bellido M, Lugo L, Roman-Blas JA, Castaneda S, Caeiro JR, Dapia S, Calvo E, Largo R, Herrero-Beaumont G (2010) Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis. Arthritis Res Ther 12(4):R152. Google Scholar
  6. 6.
    Tat SK, Pelletier JP, Lajeunesse D, Fahmi H, Duval N, Martel-Pelletier J (2008) Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: influence of osteotropic factors. Bone 43(2):284–291. Google Scholar
  7. 7.
    Massicotte F, Lajeunesse D, Benderdour M, Pelletier JP, Hilal G, Duval N, Martel-Pelletier J (2002) Can altered production of interleukin-1beta, interleukin-6, transforming growth factor-beta and prostaglandin E(2) by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients. Osteoarthritis Cartilage 10(6):491–500. Google Scholar
  8. 8.
    Yan JY, Tian FM, Wang WY, Cheng Y, Song HP, Zhang YZ, Zhang L (2014) Parathyroid hormone (1–34) prevents cartilage degradation and preserves subchondral bone micro-architecture in guinea pigs with spontaneous osteoarthritis. Osteoarthritis Cartilage 22(11):1869–1877. Google Scholar
  9. 9.
    Bellido M, Lugo L, Roman-Blas JA, Castaneda S, Calvo E, Largo R, Herrero-Beaumont G (2011) Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis. Osteoarthritis Cartilage 19(10):1228–1236. Google Scholar
  10. 10.
    Zhu S, Chen K, Lan Y, Zhang N, Jiang R, Hu J (2013) Alendronate protects against articular cartilage erosion by inhibiting subchondral bone loss in ovariectomized rats. Bone 53(2):340–349. Google Scholar
  11. 11.
    Wakita T, Mogi M, Kurita K, Kuzushima M, Togari A (2006) Increase in RANKL: OPG ratio in synovia of patients with temporomandibular joint disorder. J Dent Res 85(7):627–632Google Scholar
  12. 12.
    Kaneyama K, Segami N, Sato J, Nishimura M, Yoshimura H (2003) Expression of osteoprotegerin in synovial tissue and degradation of articular cartilage: comparison with arthroscopic findings of temporomandibular joint disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 96(3):258–262. Google Scholar
  13. 13.
    Kaneyama K, Segami N, Nishimura M, Sato J, Suzuki T, Fujimura K (2003) Osteoclastogenesis inhibitory factor/osteoprotegerin in synovial fluid from patients with temporomandibular disorders. Int J Oral Maxillofac Surg 32(4):404–407. Google Scholar
  14. 14.
    Pilichou A, Papassotiriou I, Michalakakou K, Fessatou S, Fandridis E, Papachristou G, Terpos E (2008) High levels of synovial fluid osteoprotegerin (OPG) and increased serum ratio of receptor activator of nuclear factor-kappa B ligand (RANKL) to OPG correlate with disease severity in patients with primary knee osteoarthritis. Clin Biochem 41(9):746–749. Google Scholar
  15. 15.
    Komuro H, Olee T, Kuhn K, Quach J, Brinson DC, Shikhman A, Valbracht J, Creighton-Achermann L, Lotz M (2001) The osteoprotegerin/receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand system in cartilage. Arthritis Rheum 44(12):2768–2776Google Scholar
  16. 16.
    Kwan Tat S, Amiable N, Pelletier JP, Boileau C, Lajeunesse D, Duval N, Martel-Pelletier J (2009) Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis. Rheumatology 48(12):1482–1490. Google Scholar
  17. 17.
    Moreno-Rubio J, Herrero-Beaumont G, Tardio L, Alvarez-Soria MA, Largo R (2010) Nonsteroidal antiinflammatory drugs and prostaglandin E(2) modulate the synthesis of osteoprotegerin and RANKL in the cartilage of patients with severe knee osteoarthritis. Arthritis Rheumat 62(2):478–488. Google Scholar
  18. 18.
    Hofbauer LC, Kuhne CA, Viereck V (2004) The OPG/RANKL/RANK system in metabolic bone diseases. J Musculoskelet Neuronal Interact 4(3):268–275Google Scholar
  19. 19.
    Edwards JR, Mundy GR (2011) Advances in osteoclast biology: old findings and new insights from mouse models. Nat Rev Rheumatol 7(4):235–243. Google Scholar
  20. 20.
    Shen P, Jiao Z, Zheng JS, Xu WF, Zhang SY, Qin A, Yang C (2015) Injecting vascular endothelial growth factor into the temporomandibular joint induces osteoarthritis in mice. Sci Rep 5:16244. Google Scholar
  21. 21.
    Shirakura M, Tanimoto K, Eguchi H, Miyauchi M, Nakamura H, Hiyama K, Tanimoto K, Tanaka E, Takata T, Tanne K (2010) Activation of the hypoxia-inducible factor-1 in overloaded temporomandibular joint, and induction of osteoclastogenesis. Biochem Biophys Res Commun 393(4):800–805. Google Scholar
  22. 22.
    Jiao K, Niu LN, Li QH, Ren GT, Zhao CM, Liu YD, Tay FR, Wang MQ (2015) beta2-Adrenergic signal transduction plays a detrimental role in subchondral bone loss of temporomandibular joint in osteoarthritis. Sci Rep 5:12593. Google Scholar
  23. 23.
    Liu YD, Liao LF, Zhang HY, Lu L, Jiao K, Zhang M, Zhang J, He JJ, Wu YP, Chen D, Wang MQ (2014) Reducing dietary loading decreases mouse temporomandibular joint degradation induced by anterior crossbite prosthesis. Osteoarthritis Cartilage 22(2):302–312. Google Scholar
  24. 24.
    Zhang HY, Liu YD, Yang HX, Zhang M, Liao LF, Wan XH, Wang MQ (2015) Installing and thereafter removing an aberrant prosthesis elicited opposite remodelling responses in growing mouse temporomandibular joints. J Oral Rehabil 42(9):685–692. Google Scholar
  25. 25.
    Embree M, Ono M, Kilts T, Walker D, Langguth J, Mao J, Bi Y, Barth JL, Young M (2011) Role of subchondral bone during early-stage experimental TMJ osteoarthritis. J Dent Res 90(11):1331–1338. Google Scholar
  26. 26.
    Ikeda Y, Yonemitsu I, Takei M, Shibata S, Ono T (2014) Mechanical loading leads to osteoarthritis-like changes in the hypofunctional temporomandibular joint in rats. Arch Oral Biol 59(12):1368–1376. Google Scholar
  27. 27.
    Yang T, Zhang J, Cao Y, Zhang M, Jing L, Jiao K, Yu S, Chang W, Chen D, Wang M (2015) Wnt5a/Ror2 mediates temporomandibular joint subchondral bone remodeling. J Dent Res 94(6):803–812. Google Scholar
  28. 28.
    Xu L, Guo H, Li C, Xu J, Fang W, Long X (2016) A time-dependent degeneration manner of condyle in rat CFA-induced inflamed TMJ. Am J Transl Res 8(2):556–567Google Scholar
  29. 29.
    Bolon B, Grisanti M, Villasenor K, Morony S, Feige U, Simonet WS (2015) Generalized Degenerative Joint Disease in Osteoprotegerin (Opg) Null Mutant Mice. Vet Pathol 52(5):873–882. Google Scholar
  30. 30.
    Shimizu S, Asou Y, Itoh S, Chung UI, Kawaguchi H, Shinomiya K, Muneta T (2007) Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis. Arthritis Rheumat 56(10):3358–3365. Google Scholar
  31. 31.
    Jung J-K, Sohn W-J, Lee Y, Bae YC, Choi J-K, Kim J-Y (2014) Morphological and cellular examinations of experimentally induced malocclusion in mice mandibular condyle. Cell Tissue Res 355(2):355–363Google Scholar
  32. 32.
    Walker CG, Ito Y, Dangaria S, Luan X, Diekwisch TG (2008) RANKL, osteopontin, and osteoclast homeostasis in a hyperocclusion mouse model. Eur J Oral Sci 116(4):312–318. Google Scholar
  33. 33.
    Glasson SS, Chambers MG, Van Den Berg WB, Little CB (2010) The OARSI histopathology initiative-recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage 18(Suppl 3):S17–S23. Google Scholar
  34. 34.
    Gosset M, Berenbaum F, Thirion S, Jacques C (2008) Primary culture and phenotyping of murine chondrocytes. Nat Protoc 3(8):1253–1260. Google Scholar
  35. 35.
    Blair-Levy JM, Watts CE, Fiorentino NM, Dimitriadis EK, Marini JC, Lipsky PE (2008) A type I collagen defect leads to rapidly progressive osteoarthritis in a mouse model. Arthritis Rheumat 58(4):1096–1106. Google Scholar
  36. 36.
    Hayami T, Pickarski M, Zhuo Y, Wesolowski GA, Rodan GA, Duong LT (2006) Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone 38(2):234–243. Google Scholar
  37. 37.
    Patel V, Issever AS, Burghardt A, Laib A, Ries M, Majumdar S (2003) MicroCT evaluation of normal and osteoarthritic bone structure in human knee specimens. J Orthop Res 21(1):6–13. Google Scholar
  38. 38.
    Chappard C, Peyrin F, Bonnassie A, Lemineur G, Brunet-Imbault B, Lespessailles E, Benhamou CL (2006) Subchondral bone micro-architectural alterations in osteoarthritis: a synchrotron micro-computed tomography study. Osteoarthritis Cartilage 14(3):215–223. Google Scholar
  39. 39.
    Jiao K, Niu LN, Wang MQ, Dai J, Yu SB, Liu XD, Wang J (2011) Subchondral bone loss following orthodontically induced cartilage degradation in the mandibular condyles of rats. Bone 48(2):362–371. Google Scholar
  40. 40.
    Bobinac D, Spanjol J, Zoricic S, Maric I (2003) Changes in articular cartilage and subchondral bone histomorphometry in osteoarthritic knee joints in humans. Bone 32(3):284–290Google Scholar
  41. 41.
    Yamada K, Healey R, Amiel D, Lotz M, Coutts R (2002) Subchondral bone of the human knee joint in aging and osteoarthritis. Osteoarthritis Cartilage 10(5):360–369. Google Scholar
  42. 42.
    Knowles HJ, Moskovsky L, Thompson MS, Grunhen J, Cheng X, Kashima TG, Athanasou NA (2012) Chondroclasts are mature osteoclasts which are capable of cartilage matrix resorption. Virchows Arch 461(2):205–210. Google Scholar
  43. 43.
    McManus S, Chamoux E, Bisson M, Roux S (2012) Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro. Apoptosis 17(2):121–131. Google Scholar
  44. 44.
    Wang XD, Kou XX, He DQ, Zeng MM, Meng Z, Bi RY, Liu Y, Zhang JN, Gan YH, Zhou YH (2012) Progression of cartilage degradation, bone resorption and pain in rat temporomandibular joint osteoarthritis induced by injection of iodoacetate. PloS ONE 7(9):e45036. Google Scholar
  45. 45.
    Romas E, Sims NA, Hards DK, Lindsay M, Quinn JW, Ryan PF, Dunstan CR, Martin TJ, Gillespie MT (2002) Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 161(4):1419–1427. Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Danying Chen
    • 1
    • 3
    Email author
  • Yi Liu
    • 2
    • 3
  • Zongxiang Liu
    • 2
  • Penglai Wang
    • 4
  1. 1.Zhujiang New Town Dental Clinic, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Hospital of StomatologySun Yat-sen UniversityGuangzhouChina
  2. 2.Department of EndodonticsXuzhou Stomatological HospitalXuzhouChina
  3. 3.School and Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and RegenerationTongji UniversityShanghaiChina
  4. 4.Maxillofacial SurgeryXuzhou Stomatological HospitalXuzhouChina

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