Theodore J. Yun

Osteoprotegerin and rank ligand expression in prostate cancer.

OBJECTIVES To investigate the expression of osteoprotegerin (OPG) and RANK ligand (RANKL) in human prostatic tissues. The factors regulating the increased turnover associated with prostate cancer (CaP) bone metastasis are unknown. OPG and RANKL are recently identified regulators of bone resorption and bone remodeling. METHODS Tissues from 28 patients with CaP and from 4 normal organ donors were analyzed by reverse transcriptase-polymerase chain reaction and immunohistochemistry for the expression of OPG and RANKL. RESULTS OPG and RANKL messages were detected in both normal and cancerous prostate samples. In the normal prostate, OPG protein was detected in luminal epithelial and stromal cells (5% to 65% and 15% to 70%, respectively) and RANKL immunoreactivity was observed in 15% to 50% of basal epithelial cells, 40% to 90% of luminal epithelial cells, and 70% to 100% of stromal cells. OPG was not detected in 8 of 10 primary CaP specimens; RANKL was heterogeneously expressed in 10 of 11 CaP specimens. The percentage of tumor cells expressing OPG and RANKL was significantly increased in all CaP bone metastases compared with nonosseous metastases or primary CaP. CONCLUSIONS CaP bone metastases were consistently immunoreactive for both OPG and RANKL compared with nonosseous metastases or primary CaP. The presence of these crucial bone resorption regulators in CaP bone metastases suggests a mechanism whereby CaP cells may modulate bone turnover and has profound implications for the establishment and development of CaP bone metastases in advanced disease.

Osteoprotegerin, a Crucial Regulator of Bone Metabolism, Also Regulates B Cell Development and Function

Osteoprotegerin (OPG) is a CD40-regulated gene in B cells and dendritic cells (DCs). We investigated the role of OPG in the immune system by generating opg−/− mice. Like its role as a regulator of bone metabolism, OPG also influences processes in the immune system, notably in B cell development. Ex vivo, opg−/− pro-B cells have enhanced proliferation to IL-7, and in opg−/− spleen, there is an accumulation of type 1 transitional B cells. Furthermore, opg−/− bone marrow-derived DCs are more effective in stimulating allogeneic T cells than control DCs. When challenged with a T-dependent Ag, opg−/− mice had a compromised ability to sustain an IgG3 Ag-specific response. Thus, in the immune system, OPG regulates B cell maturation and development of efficient Ab responses.

The Goldilocks conditions applied to T cell development.

The newly rearranged T cell receptor on the surface of immature thymocytes must interact with not too much and not too little affinity for self-peptide–MHC ligands to allow the cell to mature and emigrate to the lymphoid periphery. Recent experiments shed new light on how the signal is perceived as “just right”.