Abstract
The alterations of bone remodeling are typical of multiple myeloma (MM) patients where the uncoupled and unbalanced bone remodeling caused the onset of osteolytic lesions. Moreover, bone metastasis occurs in the majority of patients with breast and prostate cancer. Skeletal-related events negatively impact on quality of life by increasing the vulnerability to fractures. Several bone-targeting treatments have been developed to control bone pain and pathological fractures, including bisphosphonates and Denosumab. Nevertheless, these agents act by inhibiting osteoclast activity but do not improve bone formation. Proteasome inhibitors (PIs) have shown bone anabolic effects and encouraging results in stimulating osteoblast differentiation and bone healing. Among these, the first-in-class bortezomib and the second-generation PIs, carfilzomib, and ixazomib regulate the bone remodeling process by controlling the degradation of several bone proteins. PIs have been recently proven to also be efficacious in blocking MM-induced osteocyte death providing new possible therapeutic use in the management of bone loss. PIs have significant side effects that limit their use as bone anabolic strategy. Multiple alternative approaches have been made. The conjugation of PIs with bisphosphonates, which can target them to bone, showed good results in terms of bone anabolic activity. However, the clinical implications of these effects require further investigations.
Highlights
Inclusion criteria are listed as: (a) human mesenchymal stromal cells (MSC); (b) human osteoblast; (c) human osteocytes; (d) proteasome; (e) proteasome inhibitors; (f) studies focused on the role of proteasome on bone remodeling; (g) studies focused on the role of proteasome on bone remodeling in MM and metastatic bone cancers; (h) in vitro studies; (i) in vivo studies; (l) case reports; (m) review; (n) conference abstracts
Different OCL-derived factors are responsible for the stimulation of bone formation during this step: (i) factors released during resorption, such as transforming growth factor-beta (TGF-β), bone morphogenetic protein-2 (BMP-2), platelet-derived growth factor, (PDGF), and insulin-like growth factors; (ii) factors secreted by OCLs, such as cardiotrophin-1, sphingosine-1-phosphate, collagen triple helix repeat containing 1, and complement factor 3a; (iii) EphB4·ephrin-B2 bidirectional signaling complex expressed on OBs and OCLs, respectively
The findings reviewed suggest the proteasome inhibitors (PIs) affect bone remodeling and the activities of bone proteins
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Disruption of bone remodeling is a typical feature of metastatic bone cancers, as well as multiple myeloma (MM) and non-malignant diseases such as osteoporosis In all these pathological conditions, patients experience bone fragility and increased vulnerability to fractures with a negative impact on quality of life [2,3]. Denosumab has been recently approved by the FDA for the prevention of skeletal-related events in newly diagnosed MM patients [5] These strategies only target OCLs with no effects on bone formation. This review focuses on the main mechanisms underlying the proteasome-dependent control of bone remodeling and the anabolic effects of PIs. We summarize preclinical and clinical findings obtained with PIs in bone disease focusing on the impact on OBs and osteocytes
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