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Mechanisms of spontaneous osteoclastogenesis in cancer with bone involvement
Author(s) -
Roato Ilaria,
Grano Maria,
Brunetti Giacomina,
Colucci Silvia,
Mussa Antonio,
Bertetto Oscar,
Ferracini Riccardo
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1823fje
Subject(s) - rankl , medicine , peripheral blood mononuclear cell , osteoclast , bone pain , osteolysis , bone resorption , cancer , multiple myeloma , denosumab , spinal cord compression , cancer research , pathology , osteoporosis , spinal cord , activator (genetics) , surgery , receptor , chemistry , biochemistry , in vitro , psychiatry
Bone metastases represents a common cause of morbidity in patients suffering many types of cancer: breast, lung, kidney, prostate, and multiple myeloma. Osteolytic metastases often cause severe pain, pathologic fractures, hypercalcemia, spinal cord compression, and other nervecompression syndromes. Osteoclasts (OCs), cells deriving from granulocitic‐macrophagic lineage, are responsible for osteolysis, which may be reduced by inhibiting both OCs formation and activity. By studying bone osteolytic metastases mechanism in solid tumors, we report here our findings that cancer patients with bone involvement display an increase in osteoclasts precursors, compared with both healthy controls and cancer patients without bone metastases. Peripheral blood mononuclear cells (PBMCs) from patients with osteolytic lesions show osteoclastogenesis without adding M‐CSF, RANKL, or TNF‐α. However, these factors are necessary to generate OCs from healthy donors, non‐osteolytic patient PBMCs and T‐cell depleted PBMCs. OCs derived from cancer patients show more resorption pits than OCs from healthy donors and express genes involved in osteoclastogenesis. Our data show that a spontaneous osteoclastogenesis occurs in patients affected by osteolytic lesions and may be supported by factors released by T lymphocytes. These factors could give a priming to osteoclast precursors and promote osteoclastogenesis. In fact, T‐cell depleted PBMCs do not differentiate into OCs without adding M‐CSF and RANKL. Moreover, we do not obtain a higher number of OCs by increasing RANKL doses in cultures, and OCs and T lymphocytes mRNA level are detected for TNF‐α but not for RANKL. The addition of OPG to PBMCs cultures do not modify spontaneous osteoclastogenesis. A neutralizing anti‐TNF‐α antibody in unstimulated PBMC cultures of osteolytic cancer patients induces an inhibition of osteoclastogenesis. These data suggest that TNF‐α may be responsible for osteoclastogenesis in these tumors.