Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma.

The immune system is strongly linked to the maintenance of healthy bone. Inflammatory cytokines, specifically, are crucial to skeletal homeostasis and any dysregulation can result in detrimental health complications. Interleukins, such as interleukin 6 (IL-6), act as osteoclast differentiation modulators and as such, must be carefully monitored and regulated. IL-6 encourages osteoclastogenesis when bound to progenitors and can cause excessive osteoclastic activity and osteolysis when overly abundant. Numerous bone diseases are tied to IL-6 overexpression, including rheumatoid arthritis, osteoporosis, and bone-metastatic cancers. In the latter, IL-6 can be released with growth factors into the bone marrow microenvironment (BMM) during osteolysis from bone matrix or from cancer cells and osteoblasts in an inflammatory response to cancer cells. Thus, IL-6 helps create an ideal microenvironment for oncogenesis and metastasis. Multiple myeloma (MM) is a blood cancer that homes to the BMM and is strongly tied to overexpression of IL-6 and bone loss. The roles of IL-6 in the progression of MM are discussed in this review, including roles in bone homing, cancer-associated bone loss, disease progression and drug resistance. MM disease progression often includes the development of drug-resistant clones, and patients commonly struggle with reoccurrence. As such, therapeutics that specifically target the microenvironment, rather than the cancer itself, are ideal and IL-6, and its myriad of downstream signaling partners, are model targets. Lastly, current and potential therapeutic interventions involving IL-6 and connected signaling molecules are discussed in this review.

Cre Driver Mice Targeting Macrophages.

The Cre/loxP system is a widely applied technology for site-specific genetic manipulation in mice. This system allows for deletion of the genes of interest in specific cells, tissues, and whole organism to generate a diversity of conditional knockout mouse strains. Additionally, the Cre/loxP system is useful for development of cell- and tissue-specific reporter mice for lineage tracing, and cell-specific conditional depletion models in mice. Recently, the Cre/loxP technique was extensively adopted to characterize the monocyte/macrophage biology in mouse models. Compared to other relatively homogenous immune cell types such as neutrophils, mast cells, and basophils, monocytes/macrophages represent a highly heterogeneous population which lack specific markers or transcriptional factors. Though great efforts have been made toward establishing macrophage-specific Cre driver mice in the past decade, all of the current available strains are not perfect with regard to their depletion efficiency and targeting specificity for endogenous macrophages. Here we overview the commonly used Cre driver mouse strains targeting macrophages and discuss their major applications and limitations.