‘Educated’ Osteoblasts Reduce Osteoclastogenesis in a Bone-Tumor Mimetic Microenvironment

Abstract

Breast cancer (BC) metastases to bone disrupt the balance between osteoblasts and osteoclasts, leading to excessive bone resorption. We identified a novel subpopulation of osteoblasts with tumor-inhibitory properties, called educated osteoblasts (EOs). Here we sought to examine the effect of EOs on osteoclastogenesis during tumor progression. We hypothesized that EOs affect osteoclast development in the bone-tumor niche, leading to suppressed pre-osteoclast fusion and bone resorption. Conditioned media (CM) was analyzed for protein expression of osteoclast factors receptor activator of nuclear factor kappa-β ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor alpha (TNFα) via ELISA. EOs were co-cultured with pre-osteoclasts on a bone mimetic matrix to assess osteoclast resorption. Pre-osteoclasts were tri-cultured with EOs plus metastatic BC cells and assessed for tartrate-resistance acid phosphatase (TRAP)-positive, multinucleated (≥3 nuclei), mature osteoclasts. Tumor-bearing murine tibias were stained for TRAP to determine osteoclast number in-vivo. EO CM expressed reduced amounts of soluble TNFα and OPG compared to naïve osteoblast CM. Osteoclasts formed in the presence of EOs were smaller and less in number. Upon co-culture on a mimetic bone matrix, a 50% reduction in the number of TRAP-positive osteoclasts formed in the presence of EOs was observed. The tibia of mice inoculated with BC cells had less osteoclasts per bone surface in bones with increased numbers of EO cells. These data suggest EOs reduce osteoclastogenesis and bone resorption. The data imply EOs provide a protective effect against bone resorption in bone metastatic BC.

Stromal-Derived Extracellular Vesicles Suppress Proliferation of Bone Metastatic Cancer Cells Mediated by ERK2

“…These two studies highlight the complexity of tumor-stroma crosstalk in metastatic progression, and suggest distinct events in early-versus late-stage disease. To illustrate this point, work from our group indicates that EOs reduce osteoclastogenesis via alterations in TNFa expression (46). Additional studies investigating EOs throughout cancer progression are currently ongoing.…”

Biomarkers Associated with AIDS-Defining Malignancies in Children

“…Furthermore, the patient's overall health status must be carefully considered, as even a small respiratory infection before the examination might drastically alter the serum profile. These factors, produced by the cancer ecosystem and transported by circulation, appear to play a role in shaping the premetastatic tissue landscape, a safe niche that serves as a suitable cradle for cancer cell homing and subsequent metastasis development, as demonstrated in the cases of breast cancer and malignant melanoma (Kolb et al, 2021). High levels of IL-6, IL-10, and TNF-α in serum can predict death in patients with advanced malignant illness (Stoll et al, 2021).…”

New Generation of Meso and Antiprogestins (SPRMs) into the Osteoporosis Approach

“…Based on these findings, we know that estrogen enhances OPG production and inhibits RANKL expression, whereas testosterone and nonaromatizable androgen 5a-DHT exert a reverse action. Disturbances in OPG concentrations appear during sex hormone deficiency may serve as a protective mechanism in men or a causative agent in postmenopausal osteoporosis period in women [107,108].…”