Inhibition of osteoclast activity by complement regulation with DF3016A, a novel small-molecular-weight C5aR inhibitor

The role of C5a-C5aR1 axis in bone pathophysiology: A mini-review

“…Indeed, in vitro IL-8 stimulation has been shown to enhance IL-6 gene expression and protein production by human osteoblasts obtained from bone biopsies, indicating that IL-8-stimulated osteoblasts can produce factors that are essential for osteoclast formation (Pathak et al, 2015). Notably, the role of C5aR in regulating the first phases of osteoclast maturation has also been recently demonstrated in RAW264.7 cells (D'Angelo et al, 2020), which are murine monocytes/macrophages that upon treatment with RANKL can form multinucleated and functionally active osteoclast-like cells. Indeed, in these cells, both C5aR downregulation and antagonism-by C5aR antagonist PMX-53 and two newly synthesized allosteric C5aR antagonists, DF2593A and DF3016A-inhibited osteoclast maturation, as demonstrated by the reduced RANKL-triggered transcription of the most important osteoclast differentiation markers, such as NFATc1, MMP-9, cathepsin-K, and TRAP.…”

“…Indeed, in these cells, both C5aR downregulation and antagonism—by C5aR antagonist PMX-53 and two newly synthesized allosteric C5aR antagonists, DF2593A and DF3016A—inhibited osteoclast maturation, as demonstrated by the reduced RANKL-triggered transcription of the most important osteoclast differentiation markers, such as NFATc1, MMP-9, cathepsin-K, and TRAP. Interestingly, it was observed that, as osteoclast differentiation progressed, C5aR mRNA expression decreased, with a consequent less impact of C5aR on the regulation of later events of osteoclast fusion ( D'Angelo et al, 2020 ).…”

“…Moreover, both genetic ablation and pharmacological inhibition of C5a decreased bone metastasis in an in vivo mouse cancer model ( Ajona et al, 2018b ). Interestingly, incubation with DF3016A, a C5aR inhibitor, has been shown to diminish osteoclast-resorbing activity in vitro ( D'Angelo et al, 2020 ). Thus, it has been suggested that DF3016A may be used as a potential double-edged blade treatment to fight bone metastases from several tumors, as it can both decrease the osteoclast activity required for the formation of the bone metastatic niche and act at the level of tumor cells by reducing their homing to bone ( D'Angelo et al, 2020 ).…”

“…Interestingly, incubation with DF3016A, a C5aR inhibitor, has been shown to diminish osteoclast-resorbing activity in vitro ( D'Angelo et al, 2020 ). Thus, it has been suggested that DF3016A may be used as a potential double-edged blade treatment to fight bone metastases from several tumors, as it can both decrease the osteoclast activity required for the formation of the bone metastatic niche and act at the level of tumor cells by reducing their homing to bone ( D'Angelo et al, 2020 ). Finally, blocking C5aR signaling promotes the anti-tumor efficacy of PD-1/PD-L1 blockade, while the combined immunotherapy based on C5a and PD-1 blockade has shown synergistic effects on both lung cancer growth and metastatic progression ( Ajona et al, 2017 ).…”

Development of Synthetic Human and Mouse C5a: Application to Binding and Functional Assays In Vitro and In Vivo

“…C5aR1 has been well characterized; however, its second receptor, C5aR2, is less well understood. , C5a, via its interaction and activation of C5aR1, is a potent pro-inflammatory mediator, contributing to host defense against invading pathogens but also sustained inflammatory responses. These sustained responses are thought to lead to an exacerbation of a myriad of immune and inflammatory sterile and infectious conditions. , As a result, antagonist compounds targeting the C5a-C5aR1 interaction for treatments of these indications are being actively pursued. − Similarly, the mechanisms underlying C5a-induced C5aR2 activation are currently being investigated for ischemic, traumatic, and infections tissue injuries. − …”