Doubling Down on Wnt Signaling to Overcome Myeloma Bone Disease

Abstract

Multiple myeloma is a hematologic malignancy characterized by devastating lytic bone disease. The growth of myeloma cells in bone stimulates osteoclastic resorption, resulting in the development of osteolytic lesions that weaken the bone. These lytic lesions rarely heal, even in patients in complete remission, due to a concomitant suppression of bone formation. With improved medical treatment for multiple myeloma, patients are living longer, and proper management of the bone disease has become paramount to reducing fractures and bone pain and improving the quality of life and survival of myeloma patients. Bisphosphonates and denosumab are used in the clinic to treat myeloma bone disease but have only minor effects, if any, on repairing damaged bone. Thus, bone disease remains a major challenge in managing multiple myeloma, and new therapeutic approaches are desperately needed. Multiple signaling pathways and factors produced or induced by myeloma cells in the bone microenvironment have been shown to contribute to the abnormal bone remodeling characteristic ofmyeloma bonedisease. In the last decade, theWnt signaling pathway and its components have emerged as key regulators of bone homeostasis and repair. The binding of canonical Wnt ligands to the Wnt coreceptors low-density lipoprotein receptorrelated protein (LRP) 5 or 6 initiates a cascade of events that prevent the phosphorylation of β-catenin and its proteasomal degradation, leading to its translocation into the nucleus, where it associates with other transcription factors to control gene transcription. The Wnt signaling pathway is also modulated by extracellular antagonists such as Dickkopf-related protein 1 (DKK1), sclerostin, or sclerostin domain containing 1 (SOSTDC1), which block the binding of Wnt ligands to LRP5/6. Neutralizing antibodies to secreted antagonists of Wnt signaling, such as DKK1 and sclerostin, stimulate bone formation and can suppress bone resorption. In multiple myeloma patients, the levels of sclerostin and DKK1 are elevated. Priorwork tested anti-DKK1or anti-sclerostin antibodies in mouse models of myeloma-induced bone disease and observed promising effects on bonemass, primarily due to increases in osteoblast number and restoration of bone formation. In this issue, Simic and colleagues examine the bone effects of a novel anti-LRP6 antibody (anti-LRP6) that potentiates Wnt1-class ligand signaling. They report that anti-LRP6 increases bonemass in mice not bearing tumors and prevents the cancellous bone destruction induced by multiple myeloma cells. When combined with a neutralizing antibody against DKK1 (anti-DKK1), anti-LRP6 leads to even higher cancellous bone mass and improves bone strength in both naïve and tumor-bearing mice. These findings are consistent with the superior increases in bone mass and improved fracture repair seen with the simultaneous targeting of DKK1 and sclerostin using a bispecific neutralizing antibody in naïve mice. Interestingly, also in this issue, Choi and colleagues present a similar potentiating bone effect when simultaneously targeting two components of Wnt signaling pathways. They find that combined administration of anti-sclerostin and a neutralizing antibody against SOSTDC1, another Wnt signaling antagonist, potentiates gain in cortical but not in cancellous bone mass. One intriguing finding of the study of Simic and colleagues is anti-LRP6’s mechanism of action. They report that the beneficial skeletal effects of anti-LRP6 are primarily due to the inhibition of bone resorption. This result contrasts with the strong bone anabolic effects of anti-sclerostin or anti-DKK1 monotherapy in similar mouse models of multiple myeloma, which increase osteoblast number and bone formation rate in cancellous bone. Similarly, Choi and colleagues show that coadministration of anti-sclerostin and anti-SOSTDC1 increases bone formation in cortical bone, although whether this combination therapy affects bone resorption is not examined. The inhibition of osteoclasts seen with anti-LRP6 is not entirely surprising, asWnt signaling activation regulates the expression of the osteoclastogenic cytokines receptor activator of NF-κB ligand and osteoprotegerin. Yet the lack of a bone anabolic response when combined with anti-DKK1 is perhaps more surprising. Interestingly, Simic and colleagues hypothesize that anti-LRP6 could have direct inhibitory actions on osteoclasts. This notion was not explored in their manuscript but warrants further investigation. Antiresorptive therapy with bisphosphonates or denosumab inhibits physiological bone remodeling, thereby decreasing osteoblast formation and function. Of note, the authors demonstrate that, although treatment with anti-LRP6 inhibits bone resorption, it does not affect bone formation in naïve mice. The reasons behind this observation are unclear, and further studies are needed to determine the interplay between osteoclasts and osteoblasts in the context of antiLRP6 therapy. Nonetheless, the results by Simic and colleagues