How B cells influence bone biology in health and disease

Abstract

It is now well established that important regulatory interactions occur between the cells in the hematopoietic, immune and skeletal systems (osteoimmunology). B lymphocytes (B cells) are responsible for the generation and production of antibodies or immunoglobulins in the body. Together with T cells these lymphocytes comprise the adaptive immune system, which allows an individual to develop specific responses to an infection and retain memory of that infection, allowing for a faster and more robust response if that same infection occurs again. In addition to this immune function, B cells have a close and multifaceted relationship with bone cells. B cells differentiate from hematopoietic stem cells (HSCs) in supportive niches found on endosteal bone surfaces. Cells in the osteoblast lineage support HSC and B cell differentiation in these niches. B cell differentiation is regulated, at least in part, by a series of transcription factors that function in a temporal manner. While these transcription factors are required for B cell differentiation, their loss causes profound changes in the bone phenotype. This is due, in part, to the close relationship between macrophage/osteoclast and B cell differentiation. Cross talk between B cells and bone cells is reciprocal with defects in the RANKL-RANK, OPG signaling axis resulting in altered bone phenotypes. While the role of B cells during normal bone remodeling appears minimal, activated B cells play an important role in many inflammatory diseases with associated bony changes. This review examines the relationship between B cells and bone cells and how that relationship affects the skeleton and hematopoiesis during health and disease.

Fig. 1

Hematopoietic cell differentiation. All hematopoietic cells arise from hematopoietic stem cells (HSC) that give rise to multipotential progenitor cells (MPP, blue). B cells differentiate from the common lymphoid progenitor (CLP, green) and osteoclasts arise from the common myeloid progenitor (CMP, pink). There appears to exist a distinct lineage derived from the MPP that expresses both macrophage and B cell characteristics (B/Mφ bipotent), which can differentiate to B cells, macrophages and possibly osteoclasts (purple). (Adapted from Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, Shizuru JA, Weissman IL Ann. Rev. Immunol. 2003; 21:759–806).

Fig. 2

Transcriptional regulation of B cell differentiation. B cell differentiation is regulated, in part, by the expression of a series of transcription factors that function in a temporal manner. These transcription factors include; PU.1, Ikaros, E2A, Ebf1 and Pax5. Loss of these specific factors precludes the cells from continued maturation, and results in a developmental block of cells at the latest stage of differentiation prior to the arrest. In addition to the absence of B cells, mice deficient in PU.1, Ebf1 and Pax5 have profound changes to their skeletons. No data is available on the bone phenotype in mice deficient in Ikaros or E2A.

Fig. 3

Activated B cells induce osteoclast differentiation. B cells activated by the adaptive immune system (antigen specific) or through the innate immune system (LPS-Toll receptor) results in B cells that secrete or express on their cell surface molecules like RANKL that induce osteoclastogenesis. (Adapted from Boyle WJ, Simonet WS, Lacey DL. Nature 2003; 423:337–342).