RANK ligand and osteoprotegerin in myeloma bone disease

Abstract

Osteoclasts as effector cells in skeletal malignanciesSkeletal complications represent frequent and significant events in patients with multiple myeloma, and include osteolytic lesions, pathologic fractures, neurologic symptoms (pain, paralysis), and profound hypercalcemia. 1,2 At the cellular level, these complications are due to an excessive growth of malignant myeloma cells within the bone marrow microenvironment and their interactions with osteoblastic and osteoclastic lineage cells. 1,3,4 A consistent histologic finding in myeloma bone disease is enhanced and uncontrolled osteoclastic bone resorption adjacent to areas of plasma cell infiltrates. 2 Moreover, antiresorptive drugs that inhibit osteoclastic functions such as bisphosphonates are successfully used in patients with myeloma bone disease, indicating that osteoclasts are essential mediators in the pathogenesis of myeloma bone disease. 5 In the past 5 years, an essential cytokine system for osteoclast biology has been characterized. 6,7 This system consists of a ligand, receptor activator of NF-B ligand (RANKL), 8,9 a cellular receptor, RANK, 8,10 and a soluble decoy receptor, osteoprotegerin (OPG). 11 While RANKL stimulates several aspects of osteoclast function, thus enhancing bone resorption, OPG blocks RANKL, and prevents bone resorption. 9,12 Abnormalities of this system have been implicated in the pathogenesis of various skeletal diseases characterized by enhanced osteoclastic activity and increased bone resorption, including osteolytic metastasis and tumor-associated hypercalcemia. 13 RANKL and OPG in bone cell biologyOsteoclasts are derived from macrophagic/monocytic lineage cells and represent differentiated, multinucleated cells specialized in resorbing bone. 6,7 Recently, the essential cytokines of osteoclast biology have been identified and extensively characterized. Osteoclastic lineage cells express RANK, a member of the tumor necrosis factor receptor superfamily. 8,10 Following activation of RANK by its ligand, RANKL, differentiation, proliferation, and survival of preosteoclast is enhanced, osteoclastic fusion and activation is promoted, and osteoclastic apoptosis is suppressed, resulting in a marked increase of the number and activity of osteoclasts. 9,12 RANKL is mainly produced by osteoblastic lineage cells, 14 immune cells, 8,15 and some cancer cells. 16,17 This provides the cellular and molecular basis for osteoblast-osteoclast cross-talks, which are crucial for an orderly sequence of bone resorption and formation during bone remodeling. 14 However, RANKL production by immune and cancer cells also forms the basis of skeletal complications of inflammatory and malignant diseases, because activated T cells and cancer cells are able to directly activate RANK on osteoclasts by virtue of expressing RANKL. 4,7 The potent stimulatory effects of RANKL on RANK are counteracted by a safeguard mechanism. Many cell types-in the bone marrow microenvironment, mainly osteoblastic lineage cells-secrete OPG, which acts as a decoy receptor and bloc...

Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma

“…12 The imbalance in RANKL (receptor activator of nuclear factor kappaB ligand)-toosteoprotegerin ratio in the bone marrow microenvironment is a crucial mechanism leading to osteoclast activation. 13 The increased bone resorption can be measured by various collagen type-I degradation markers. 14 In various studies, it was shown that serum carboxy-terminal telopeptide of type-1 collagen (ICTP) is a sensitive and specific marker of increased bone resorption [15][16][17] and has a prognostic impact for overall survival (OS) in MM patients.…”

In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

“…One hypothesis is that SH-SY5Y cells could have the capability of neutralizing OPG, as already described for other tumors. 29 Some authors have demonstrated that myeloma cells adopt mechanisms to inhibit the production of OPG or its availability in the bone microenvironment. Syndecan-1, a proteoglycan heparan sulfate expressed on the membrane of myeloma cells, binds inactive OPG by the same binding domain as heparin; then, OPG is internalized and degraded by lysosomes.…”

Treatment strategies for bone disease

“…Other cell sources for RANKL in addition to osteoblasts in myeloma include T lymphocytes 15 as well as myeloma cells themselves, which have been reported to express low levels of RANKL. [16][17][18][19] Pearse and co-workers 20 were the first to clearly demonstrate that RANKL expression was upregulated in bone marrow biopsies in patients with myeloma while OPG was decreased. They detected RANKL expression in cells in the marrow microenvironment rather than the myeloma cells.…”