Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis

Abstract

Bone metastasis (BM) is a dismal complication of cancer that frequently occurs in patients with advanced carcinomas and that often manifests as an osteolytic lesion. In bone, tumor cells promote an imbalance in bone remodeling via the release of growth factors that, directly or indirectly, stimulate osteoclast resorption activity. However, carcinoma cells are also characterized by an altered metabolism responsible for a decrease of extracellular pH, which, in turn, directly intensifies osteoclast bone erosion. Here, we speculated that tumor-derived acidosis causes the osteoblast–osteoclast uncoupling in BM by modulating the pro-osteoclastogenic phenotype of osteoblasts. According to our results, a low pH recruits osteoclast precursors and promotes their differentiation through the secretome of acid-stressed osteoblasts that includes pro-osteoclastogenic factors and inflammatory mediators, such as RANKL, M-CSF, TNF, IL-6, and, above the others, IL-8. The treatment with the anti-IL-6R antibody tocilizumab or with an anti-IL-8 antibody reverted this effect. Finally, in a series of BM patients, circulating levels of the osteolytic marker TRACP5b significantly correlated with IL-8. Our findings brought out that tumor-derived acidosis promotes excessive osteolysis at least in part by inducing an inflammatory phenotype in osteoblasts, and these results strengthen the use of anti-IL-6 or anti-IL-8 strategies to treat osteolysis in BM.

Photoluminescent carbon dots (PCDs) from sour apple: a biocompatible nanomaterial for preventing UHMWPE wear-particle induced osteolysis via modulating Chemerin/ChemR23 and SIRT1 signaling pathway and its bioimaging application

“…In a scenario wherein arthroplasties are progressively having operated on transplant patients, osteolysis is the major cause of errors during joint replacement prosthesis has received much interest [ 1 ]. Wear particle-induced osteolysis caused by ultra-high molecular weight polyethylene has been the practice through which reconstructive wreckage statically released from the substratum of prosthetic joint surfaces provokes an inflammatory system that favors bone catabolism, culminating in weakening of prosthetics and imminent downfall or cracking [ 2 , 3 ]. Wear particles made of ultra-high molecular weight polyethylene (UHMWPE) have now been identified as among the most common causes of aseptic loosening in total orthopedic implants [ 4 ].…”

Acid Microenvironment in Bone Sarcomas

“…[50]); carcinoma cells metastasizing to the bone share with bone sarcoma cells different mechanisms of proton extrusion, including the expression of V 1 B 2 and V 0 c V-ATPase subunits, CAIX, MCT1, and MCT4. As an example, we have recently found mRNA expression of CAIX in breast and renal carcinoma cell lines, with a significant increase under reduced oxygen conditions with respect to normoxia [50,56]. Additionally, different isoforms of V-ATPase, including the V 1 C 1 [57] and the V 1 B 2 and V 1 G 1 subunits [58], are expressed by breast carcinoma cells with a specific tropism for bone.…”

“…Other factors, such as interleukin 1 (IL-1), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNFa), parathyroid hormone-related protein (PTHrP), or transforming growth factorbeta (TGFb), mediate RANKL receptor (RANK) expression on the surface of osteoclasts, thereby favouring osteoclast maturation and activation [59]. Furthermore, we have recently demonstrated that a low pH further induces osteoclast activity, both directly and indirectly, by stimulating osteoblasts to secrete pro-osteoclastogenic paracrine mediators such as IL-8 and IL-6 [56].…”

Dickkopf‑3 and β‑catenin play opposite roles in the Wnt/β‑catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis

“…Maruotti et al ( 5 ) revealed that osteoblast disorders play a crucial role in the pathogenesis of OA, stimulating the osteoblast-induced production of large transcription factor quantities, growth factors and other proteins involved in OA pathogenesis. In addition, Di Pompo et al ( 6 ) previously reported that osteoblasts promoted the secretion of osteoclastic cytokines and inflammatory mediators in an acidic environment (pH 6.8), further exacerbating OA.…”