Osteoclastogenesis and Factors Produced by the Bone Extracellular Matrix Are Altered by Educated Osteoblasts in a Bone-Tumor Mimetic Microenvironment
Abstract
Osteoblasts and osteoclasts work together to maintain bone homeostasis. Under normal conditions, there is a balance between osteoblast bone deposition and osteoclast bone resorption. Under disease conditions, such as in late-stage bone metastatic breast cancer, breast cancer cells disrupt the communication between osteoblasts and osteoclasts causing an imbalance in bone homeostasis. In this way, osteoclast-dependent bone resorption occurs more frequently than osteoblast-dependent bone deposition, resulting in osteolytic lesion formation. Breast cancer cells utilize this disruption in osteoblast and osteoclast communication to promote tumor outgrowth in bone. Our lab has previously identified a novel subpopulation of osteoblasts in the bone-tumor microenvironment called ‘educated’ osteoblasts (EOs) that exhibit altered function compared to ‘uneducated’ or naïve osteoblasts. We found that crosstalk between EOs and breast cancer cells reduced breast cancer cell proliferation and changed the molecular landscape of the bone microenvironment to favor tumor inhibition. The aim of this study was to identify how osteoclasts interact with EOs and how this interaction affects osteoclastogenesis. We found that pre-osteoclast interaction with EOs reduced osteoclastogenesis, resulting in osteoclasts that were less in number, smaller in size, and had reduced resorptive activity compared to osteoclasts produced in the presence of naïve osteoblasts. Additionally, we found that EOs have altered expression of factors associated with osteoclast differentiation and fusion, which mediated alterations seen in osteoclast formation. In murine tibia, we found that increased number of EOs led to the production of osteoclasts that were smaller in size compared to large osteoclasts formed in bones containing increased numbers of naïve osteoblasts. We further demonstrate that these effects may be modulated, in part, by TNFα from EOs. We also investigated the expression of bone extracellular matrix factors, collagen type I and matrix metalloproteinase-9 (MMP-9) in EOs. We found that EOs have altered expression of collagen type I and MMP-9, supporting prior evidence from our laboratory demonstrating alterations in EO protein expression. These results highlight the importance of tumor-stromal cell interactions and the effect these interactions have on the bone-tumor microenvironment.
Subject Area
Cellular biology|Molecular biology
Recommended Citation
Kolb, Alexus D, "Osteoclastogenesis and Factors Produced by the Bone Extracellular Matrix Are Altered by Educated Osteoblasts in a Bone-Tumor Mimetic Microenvironment" (2021). ProQuest ETD Collection - Thomas Jefferson University. AAI28645230.
https://jdc.jefferson.edu/dissertations/AAI28645230
