Oncostatin M: Dual Regulator of the Skeletal and Hematopoietic Systems.

ABSTRACT

PURPOSE OF THE REVIEW The bone and hematopoietic tissues coemerge during development and are functionally intertwined throughout mammalian life. Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family produced by osteoblasts, bone marrow macrophages, and neutrophils. OSM acts via two heterodimeric receptors comprising GP130 with either an OSM receptor (OSMR) or a leukemia inhibitory factor receptor (LIFR). OSMR is expressed on osteoblasts, mesenchymal, and endothelial cells and mice deficient for the Osm or Osmr genes have both bone and blood phenotypes illustrating the importance of OSM and OSMR in regulating these two intertwined tissues. RECENT FINDINGS: OSM regulates bone mass through signaling via OSMR, adaptor protein SHC1, and transducer STAT3 to both stimulate osteoclast formation and promote osteoblast commitment; the effect on bone formation is also supported by action through LIFR. OSM produced by macrophages is an important inducer of neurogenic heterotopic ossifications in peri-articular muscles following spinal cord injury. OSM produced by neutrophils in the bone marrow induces hematopoietic stem and progenitor cell proliferation in an indirect manner via OSMR expressed by bone marrow stromal and endothelial cells that form hematopoietic stem cell niches. OSM acts as a brake to therapeutic hematopoietic stem cell mobilization in response to G-CSF and CXCR4 antagonist plerixafor. Excessive OSM production by macrophages in the bone marrow is a key contributor to poor hematopoietic stem cell mobilization (mobilopathy) in people with diabetes. OSM and OSMR may also play important roles in the progression of several cancers. It is increasingly clear that OSM plays unique roles in regulating the maintenance and regeneration of bone, hematopoietic stem and progenitor cells, inflammation, and skeletal muscles. Dysregulated OSM production can lead to bone pathologies, defective muscle repair and formation of heterotopic ossifications in injured muscles, suboptimal mobilization of hematopoietic stem cells, exacerbated inflammatory responses, and anti-tumoral immunity. Ongoing research will establish whether neutralizing antibodies or cytokine traps may be useful to correct pathologies associated with excessive OSM production.