Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases

Abstract

Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease.

Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone

“…34,35 We hypothesized that enhanced adipocyte lineage cells in new bone sites would contribute to MM dissemination through similar mechanisms. Indeed, we found that both preadipocyte and mature adipocyte secreted factors could attract MM cells, particularly through MCP-1 and SDF-1a.…”

New therapeutic targets for cancer bone metastasis

“…The number of marrow adipocytes increases greatly with aging and obesity, which are also risk factors for the development of metastatic cancers. Marrow adipocytes secrete hormones, cytokines and fatty acids that may have profound effects on hematopoietic niches, neighboring bone cells and inflammation, hence shaping the local milieu, hematopoiesis and skeletal homeostasis [147]. It has been suggested that tumor cells can also be attracted to marrow adipocytes and affected by adipokines.…”

“…It has been suggested that tumor cells can also be attracted to marrow adipocytes and affected by adipokines. The interaction between these two cell types may create a chronic inflammatory environment that is pro-tumorigenic, as well as the translocation of adipocyte-stored lipids to the metastatic tumor cells, causing an increased motility in tumor cells [147, 148, 149]. …”

Prostaglandin E2 impairs osteogenic and facilitates adipogenic differentiation of human bone marrow stromal cells

“…Endogenous PGE 2 formation was locally increased after bone fractures, the inhibition of PGE 2 formation impairs bone healing and local administration of PGE 2 stimulated bone formation in animal studies [5]. Otherwise, the over-exposition of bones with pro-inflammatory mediators, systemic and long-term chronic inflammation causes impaired or decelerated bone healing or even Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/plefa more bone/joint destructions as known from osteo-or rheumatoid arthritis [6][7][8][9] and an imbalance of osteoblastogenesis and adipogenesis in the bone marrow cell population at the expense of osteoblast [10,11].…”