Histochemistry and Cell Biology

, Volume 149, Issue 4, pp 405–415 | Cite as

Pathologic conditions of hard tissue: role of osteoclasts in osteolytic lesion

  • Riko Kitazawa
  • Ryuma Haraguchi
  • Mana Fukushima
  • Sohei Kitazawa


Hard tissue homeostasis is regulated by the balance between bone formation by osteoblasts and bone resorption by osteoclasts. This physiologic process allows adaptation to mechanical loading and calcium homeostasis. Under pathologic conditions, however, this process is ill-balanced resulting in either over-resorption or over-formation of hard tissue. Local over-resorption by osteoclasts is typically observed in osteolytic metastases of malignancies, autoimmune arthritis, and giant cell tumor of bone (GCTB). In tumor-related local osteolysis, tumor-derived osteoclast-activating factors induce bone resorption not by directly acting on osteoclasts but by indirectly upregulating receptor activator of NFκB ligand (RANKL) on osteoblastic cells. Similarly, synovial tissue in the autoimmune arthritis model does overexpress RANKL and contains numerous osteoclast precursors, and like a landing craft, when it comes in contact with eroded bone surfaces, osteoclast precursors are immediately polarized to become mature osteoclasts, inducing rapidly progressive bone destruction at a late stage of the disease. GCTB, on the other hand, is a common primary bone tumor, usually arising at the metaphysis of the long bone in young adults. After the discovery of RANKL, the concept of GCTB as a tumor of RANKL-expressing stromal cells was established, and comprehensive exosome studies finally disclosed the causative single-point mutation at histone H3.3 (H3F3A) in stromal cells. Thus, osteolytic lesions under various pathological conditions are ultimately attributable to the overexpression of RANKL, which opens up a common, practical and useful therapeutic target for diverse osteolytic conditions.


Osteoclasts RANKL Bone resorption Cancer Rheumatoid arthritis Giant cell tumor of bone 



This study was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (to RK, RH and SK).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Diagnostic PathologyEhime University HospitalToonJapan
  2. 2.Department of Molecular Pathology, Graduate School of MedicineEhime University Graduate School of MedicineToonJapan

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