Expression of parathyroid hormone (PTH)-related peptide (PTHrP) and PTH/PTHrP receptor in osteoclast-like giant cells

Osteoclast-like giant cells (OCGC), which resemble osteoclasts at both the morphologic and immunohistochemical levels, develop in neoplastic tissue. In bone marrow, parathyroid hormone (PTH)-related peptide (PTHrP) can induce osteoclast differentiation by stimulating osteoclast progenitors through the PTH/PTHrP receptor (PPR). To evaluate the possible involvement of PTHrP in OCGC formation in tumors, we analyzed both PTHrP and PPR expression by immunohistochemistry in giant cell tumor of bone (GCTB) and anaplastic thyroid cancer (ATC) containing OCGC. In all cases of either GCTB (n = 5) or ATC (n = 4), intense staining for PTHrP was found in OCGC, but only faintly in mononuclear cells. PPR expression in OCGC was also demonstrated in 3 cases of GCTB and 2 cases of ATC. Double staining for PPR and proliferating cell nuclear antigen (PCNA) revealed that PPR was mainly expressed by PCNA-negative mononuclear cells and OCGC in these tumors. This suggests that OCGC might be derived from non-proliferating mononuclear cells by PTHrP stimulation via PPR. Furthermore, the profiles of PTHrP and PPR expression in OCGC were compared with those in the neoplastic GC found in malignancy (n = 6), osteoclasts in bone with osteoarthritis (n = 5), reactive GC, including Langhans-type and foreign body-type in pulmonary tuberculosis (n = 8), and ruptured epidermal cyst (n = 14) in order to clarify whether their distribution pattern was unique to OCGC. In all cases of malignancy, expression of both PTHrP and PPR was observed ubiquitously in neoplastic GC and mononuclear cells regardless of PCNA immunoreactivity. In contrast, in osteoclasts and reactive GC, PTHrP immunoreactivity was seen in all cases and in 7 of 22 cases, respectively, but no PPR expression was observed in either. In situ hybridization confirmed PTHrP expression at the transcriptional level in OCGC and neoplastic GC, but not in osteoclasts. Thus, although PTHrP expression was commonly observed in various types of multinucleated giant cells, their immunohistochemical profiles for PPR were distinct. We conclude that PPR might play a role during OCGC formation in GCTB and ATC.