CD14− mononuclear stromal cells support (CD14+) monocyte–osteoclast differentiation in aneurysmal bone cyst

Abstract

Aneurysmal bone cyst (ABC) is a benign osteolytic bone lesion in which there are blood-filled spaces separated by fibrous septa containing giant cells. The nature of the giant cells in this lesion and the mechanism of bone destruction in ABC is not certain. In this study, we have analysed several characteristics of mononuclear and multinucleated cells in the ABC and examined the cellular and molecular mechanisms of ABC osteolysis. The antigenic and functional phenotype of giant cells in ABC was determined by histochemistry/immunohistochemistry using antibodies to macrophage and osteoclast markers. Giant cells and CD14 þ and CD14À mononuclear cells were isolated from ABC specimens and cultured on dentine slices and coverslips with receptor activator of nuclear factor kB ligand (RANKL) þ /À macrophage-colony stimulating factor (M-CSF) and functional and cytochemical evidence of osteoclast differentiation sought. Giant cells in ABC expressed an osteoclast-like phenotype (CD51 þ , CD14À, cathepsin K þ , TRAP þ ) and were capable of lacunar resorption, which was inhibited by zoledronate, calcitonin and osteoprotegerin (OPG). When cultured with RANKL ± M-CSF, CD14 þ , but not CD14À, mononuclear cells differentiated into TRAP þ multinucleated cells that were capable of lacunar resorption. M-CSF was not necessary for osteoclast formation from CD14 þ cell cultures. CD14À cells variably expressed RANKL, OPG and M-CSF but supported osteoclast differentiation. Our findings show that the giant cells in ABC express an osteoclast-like phenotype and are formed from CD14 þ macrophage precursors. CD14À mononuclear stromal cells express osteoclastogenic factors and most likely interact with CD14 þ cells to form osteoclast-like giant cells by a RANKL-dependent mechanism.Laboratory Investigation (2012) 92, 600-605; doi:10.1038/labinvest.2012.5; published online 13 February 2012 KEYWORDS: aneurysmal bone cyst (ABC); bisophosphonate; bone resorption; giant cell; osteoclast Benign and malignant tumours that contain numerous osteoclast-like giant cells frequently arise in bone and are categorised on the basis of tissue location and histomorphology. 1,2 The mechanism whereby giant cells accumulate and contribute to the osteolysis that accompanies growth of these tumours in bone is not certain. Primary aneurysmal bone cyst (ABC) is a benign cystic giant cell-rich tumour that arises most commonly in the metaphyseal region of a long bone; 1,2 the cysts are filled with blood and the fibrous cyst wall contains fibroblast-like stromal cells, scattered macrophages and osteoclast-like giant cells. The lesion most commonly arises in the first two decades of life and is a clonal proliferation associated with a characteristic rearrangement of the short arm of chromosome 17. [3][4][5] Osteoclasts are formed from marrow-derived circulating precursors, which express a monocyte/macrophage phenotype. 6,7 These mononuclear phagocyte precursors express the receptor activator of nuclear factor kB (RANK) and, in the presence of macrophage-colony stimulating...

Denosumab in patients with aneurysmal bone cysts: A case series with preliminary results

“… 37 The positive results with denosumab in the treatment of GCTB 35 , 37 as well as the clear immunohistochemical similarity and relationship between GCTB and ABCs 31 , 35 justify the hypothesis that denosumab may also have positive effects on ABCs. 42 …”

Giant cell tumour of the distal radius/ulna: response to pre-operative treatment with short-term denosumab

“…There are a few previous case reports describing the effect of denosumab treatment on GCTB of the distal radius. A beneficial effect of denosumab was noted on a GCTB of the distal radius [ 24 ] and a locally aggressive giant cell-containing lesion of the radius diagnosed as aneurysmal bone cyst, a lesion which is also known to contain stromal cells that express RANKL [ 25 , 26 ]. Matcuk et al [ 27 ] noted rapid recurrence and aggressive growth of a GCTB after the cessation of long-term denosumab therapy, indicating that surgery is important in managing these tumours.…”

Therapeutic Management of a Substantial Pelvic Aneurysmatic Bone Cyst Including the Off-Label Use of Denosumab in a 35-Year-Old Female Patient

“…Clinical data has already shown the successful therapeutic use of Denosumab in the context of osteoporosis, bone metastases, and recently giant cell tumor, which share immunohistochemical attributes with ABC. Furthermore, recent studies suggested RANKL to play an important part in ABC as well which could explain Denosumab's effects on ABC [ 15 , 22 – 24 ].…”