Cell-molecular interactions at the border of articular cartilage and subchondral bone

Nataliya Yakovenchuk


It has been proven that subchondral bone and articular cartilage are structurally and metabolically related. The molecular triad OPG/RANK/RANKL controls the differentiation and biological function of osteoclasts. It was established that the level of expression of these molecules by chondrocytes depends on the stage of pathological changes. Objective: to study the expression of RANKL and OPG in the cells of the articular cartilage and subchondral bone obtained after hip replacement of 56 patients with hip joint arthritis and in an animal experiment. Methods: сhanges in articular cartilage and bone tissue were induced in animals by ovariectomy. Clinical and experimental material was studied by histological methods using scanning microscopy, immunohistochemical evaluation of RANKL and OPG. Results: OPG and RANKL expression in early arthritic disorders was detected in rats, mainly in the superficial area of articular cartilage. In clinical material, RANKL expression was noted only in individual chondrocytes of preserved articular cartilage. The color intensity was low. An increased expression of RANKL by osteocytes was found in the osteochondral junction zone. The most pronounced immunoreactivity was noted in chondrocytes, especially in isogenic groups, throughout the preserved articular cartilage. Osteocytes and single osteoblasts located on the marginal surface of bone trabeculae were expressed in OPG bone tissue. In the intertrabecular spaces, an intense reaction is fixed in the cells around the vessels. Conclusions: an increase in the RANKL/OPG ratio was noted in chondrocytes of articular cartilage already in the early stages of arthrosis. Significant changes in the subchondral bone microarchitecture with the presence of immunopositive cells indicate active remodeling processes, which are a reflection of the ab­normal expression of RANKL/OPG by cells of bone and cartilage tissue under conditions of arthritis against a background of reduced bone mineral density.


osteoarthrosis; osteochondral connection; RANKL; OPG


Korzh, M. O., Dedukh, N. V., & Yakovenchuk, N. N. (2013). Osteoporosis and osteoarthrosis: pathogenetically interrelated diseases? (review of literature). Orthopedics, Traumatology and Prosthetics, 4, 102–110. doi: 10.15674/0030-598720134102-110 (in Russian)

Findlay, D. M., & Atkins, G. J. (2014). Osteoblast-Chondrocyte Interactions in Osteoarthritis. Current Osteoporosis Reports, 12 (1), 127–134. doi:10.1007/s11914-014-0192-5

Yuan, X., Meng, H., Wang, Y., Peng, J., Guo, Q., Wang, A., & Lu, S. (2014). Bone-cartilage interface crosstalk in osteoarthritis: potential pathways and future therapeutic strategies. Osteoarthritis and Cartilage, 22 (8), 1077–1089. doi:10.1016/j.joca.2014.05.023

Deveza, L. A., Bierma-Zeinstra, S. M., Van Spil, W. E., Oo, W. M., Saragiotto, B. T., Neogi, T., … Hunter, D. J. (2018). Efficacy of bisphosphonates in specific knee osteoarthritis subpopulations: protocol for an OA Trial Bank systematic review and individual patient data meta-analysis. BMJ Open, 8 (12), e023889. doi: 10.1136/bmjopen-2018-023889

Tat, S. K., Pelletier, J., 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. doi: 10.1016/j.bone.2008.04.006

Burr, D. B., & Gallant, M. A. (2012). Bone remodelling in osteoarthritis. Nature Reviews Rheumatology, 8 (11), 665–673. doi:10.1038/nrrheum.2012.130

Yu, D., Xu, J., Liu, F., Wang, X., Mao, Y., &Zhu Z. (2016). Subchondral bone changes and the impacts on joint pain and articular cartilage degeneration in osteoarthritis. Clinical and Experimental Rheumatology, 34 (5), 929–934. doi: 10.1038_s41598-01.

Xiao, Z., Su, G., Hou, Y., Chen, S., & Lin, D. (2018). Cartilage degradation in osteoarthritis: A process of osteochondral remodeling resembles the endochondral ossification in growth plate? Medical Hypotheses, 121, 183–187. doi:10.1016/j.mehy.2018.08.023

Arias, C. F., Herrero, M. A., Echeverri, L. F., Oleaga, G. E., & López, J. M. (2018). Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms. PLOS ONE, 13 (9), e0204171. doi:10.1371/journal.pone.0204171

Eriksen E. F. (2010). Cellular mechanisms of bone remodeling. Reviews i n e ndocrine & metabolic d isorders, 11 (4), 219–227. doi: 10.1007/ s11154-010-9153-1.

Sharma, A., Jagga, S., Lee, S., & Nam, J. (2013). Interplay between cartilage and subchondral bone contributing to pathogenesis of osteoarthritis. International Journal of Molecular Sciences, 14(10), 19805-19830. doi:10.3390/ijms141019805

Kenkre J. S., & Bassett, J. (2018). The bone remodelling cycle. Annals of Clinical Biochemistry, 55 (3), 308–327. doi: 10.1177/0004563218759371.

Boyce, B. F., & Xing, L. (2008). Functions of RANKL/RANK/OPG in bone modeling and remodeling. Archives of Biochemistry and Biophysics, 473 (2), 139–146. doi: 10.1016/

Weitzmann, M. N. (2013). The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis. Scientifica, 2013, 1–29. doi: 10.1155/2013/125705

Kohli, S., & Kohli, V. (2011). Role of RANKL-RANK/osteoprotegerin molecular complex in bone remodeling and its immunopathologic implications. Indian Journal of Endocrinology and Metabolism, 15 (3), 175. doi:10.4103/2230-8210.83401

Komuro, H., Olee, T., Kuhn, K., Quach, J., Brinson, D. C., Shikhman, A., … Lotz, M. (2001). The osteoprotegerin/receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand system in cartilage. Arthritis & Rheumatism, 44 (12), 2768–2776. doi: 10.1002/1529-0131(200112)44:12<2768::aid-art464>;2-i

Upton, A. R., Holding, C. A., Dharmapatni, A. A., & Haynes, D. R. (2011). The expression of RANKL and OPG in the various grades of osteoarthritic cartilage. Rheumatology International, 32 (2), 535–540. doi: 10.1007/s00296-010-1733-6

Maria J. Martínez-Calatrava, Ivan Prieto-Potín, Jorge A. Roman-Blas, Lidia Tardio, Raquel Largo & Gabriel Herrero-Beaumont (2012). RANKL synthesized by articular chondrocytes contributes to juxta-articular bone loss in chronic arthritis. Arthritis Research & Therapy, 14 (3), R149. doi: 10.1186/ar3884.

Wang, B., Jin, H., Shu, B., Mira, R. R., & Chen, D. (2015). Chondrocytes-Specific Expression of Osteoprotegerin Modulates Osteoclast Formation in Metaphyseal Bone. Scientific Reports, 5(1). doi:10.1038/srep13667

Zeng, J., Wang, Z., Ma, L., Meng, H., Yu, H., Cheng, W., … Guo, A. (2016). Increased receptor activator of nuclear factor κβ ligand/osteoprotegerin ratio exacerbates cartilage destruction in osteoarthritis in vitro. Experimental and Therapeutic Medicine, 12 (4), 2778–2782. doi:10.3892/etm.2016.3638

Kovács, B., Vajda, E., & Nagy, E. E. (2019). Regulatory Effects and Interactions of the Wnt and OPG-RANKL-RANK Signaling at the Bone-Cartilage Interface in Osteoarthritis. International Journal of Molecular Sciences, 20(18), E4653. doi: 10.3390/ijms20184653

Povoroznуuk, V. V, Dedukh, N. V, Grуgorуeva, V. V., & Gopkalova, I. V. (2012). Experimental osteoporosis. Kiev. [in Russian]

European Convention for the Protection of Vertebrate Animals Used for Research and Other Scientific Purposes. Strasbourg, March 18, 1986: official translation [Electronic resource]. Verkhovna Rada of Ukraine. Retrieved from http: zakon. (in Ukrainian)

On the Protection of Animals from Cruelty: Law of Ukraine № 3447-IV of 21.02.2006 [Electronic resource]. Verkhovna Rada of Ukraine. Retrieved from http: zakon. (in Ukrainian)

Kellgre, J. H., & Lawrence, J. S. (1957). Radiological. Assessment of Osteo-Arthrosis Annals of the Rheumatic Diseases, 16, 494–502.

Sarkisov, D. S., & Perov ,Yu. L. (1996). Microscopic technology. Moscow: Medicine. [in Russian]

Allred, D. C., Harvey, J. M., Berardo, M. & Clark, G. M. (1998). Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Modern Pathology, 11 (2), 155–168.

Gerwin, N., Bendele, A., Glasson, S., & Carlson, C. (2010). The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in the rat. Osteoarthritis and Cartilage, 18, S24–S34. doi: 10.1016/j.joca.2010.05.030

Chand, P., Anubha, G., Singla, V., & Rani, N. (2018). Evaluation of immunohistochemical profile of breast cancer for prognostics and therapeutic use. Nigerian Journal of Surgery, 24 (2), 100. doi: 10.4103/njs.njs_2_18

Lv, Y., Xia, J., Chen, J., Zhao, H., Yan, H., Yang, H., & Chen, X. (2014). Effects of pamidronate disodium on the loss of osteoarthritic subchondral bone and the expression of cartilaginous and subchondral osteoprotegerin and RANKL in rabbits. BMC Musculoskeletal Disorders, 15 (370). doi: 10.1186/1471-2474-15-370

Li, G., Yin, J., Gao, J., Cheng, T. S., Pavlos, N. J., Zhang, C., & Zheng, M. H. (2013). Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes. Arthritis Research & Therapy, 15 (6), 223. doi: 10.1186/ar4405

Kauppinen, S., Karhula, S., Thevenot, J., Ylitalo, T., Rieppo, L., Kestilä, I., & Nieminen, H. (2019). 3D morphometric analysis of calcified cartilage properties using micro-computed tomography. Osteoarthritis and Cartilage, 27 (1), 172–180. doi:10.1016/j.joca.2018.09.009

Povoroznyuk, V. V., & Grigoryeva, N. V. (2012). Osteoarthrosis in postmenopausal women: risk factors and connection with bone tissue. Endocrinology, 6, 8, 64–71. [in Russian]

Oláh, T., & Madry, H. (2018). The Osteochondral Unit: The Importance of the Underlying Subchondral Bone. In J. Farr, A. Gomoll (eds.). Springer, Cham. doi:10.1007/978-3-319-77152-6_2

Upton, A. R., Holding, C. A., Dharmapatni, A. A., & Haynes, D. R. (2011). The expression of RANKL and OPG in the various grades of osteoarthritic cartilage. Rheumatology International, 32 (2), 535–540. doi: 10.1007/s00296-010-1733-6

Maruotti, N., Corrado, A., & Cantatore, F. P. (2017). Osteoblast role in osteoarthritis pathogenesis. Journal of Cellular Physiology, 232 (11), 2957–2963. doi: 10.1002/jcp.25969

Bolon, B., Grisanti, M., Villasenor, K., Morony, S., Feige, U., & Simonet, W. S. (2015). Generalized degenerative joint disease in osteoprotegerin (Opg) null mutant mice. Veterinary Pathology, 52 (5), 873–882. doi: 10.1177/0300985815586221

Tat, S. K., Pelletier, J., Velasco, C. R., Padrines, M., & Martel-Pelletier, J. (2009). New Perspective in Osteoarthritis: The OPG and RANKL System as a Potential Therapeutic Target? The Keio Journal of Medicine, 58 (1), 29–40. doi: 10.2302/kjm.58.29

J. Menetrey, F. Unno-Veith, H. Madry, I. van Breuseghem (2010). Epidemiology and imaging of the subchondral bone in articular cartilage repair. Knee Surgery, Sports Traumatology, Arthroscopy, 18 (4), 463–471. doi: 10.1007/s00167-010-1053-0

Madry, H., Van Dijk, C. N., & Mueller-Gerbl, M. (2010). The basic science of the subchondral bone. Knee Surgery, Sports Traumatology, Arthroscopy, 18 (4), 419–433. doi:10.1007/s00167-010-1054-z

Yakovenchuk, N. M., & Dyedukh, N. V. (2017). Morphology of joint cartilage and subhondral bone plate after modeling osteoporosis. Bulletin of problems of biology and medicin, 4, 3, 324–327. DOI: 10.29254/2077-4214-2017-4-3-141-324-327 [in Ukrainian]

Stewart, H. L., & Kawcak, C. E. (2018). The Importance of Subchondral Bone in the Pathophysiology of Osteoarthritis. Frontiers in Veterinary Science, 5. doi:10.3389/fvets.2018.00178

Fell, N., Lawless, B., Cox, S., Cooke, M., Eisenstein, N., Shepherd, D., & Espino, D. (2019). The role of subchondral bone, and its histomorphology, on the dynamic viscoelasticity of cartilage, bone and osteochondral cores. Osteoarthritis and Cartilage, 27 (3), 535–543. doi: 10.1016/j.joca.2018.12.006

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