Bone marrow is the main hematopoietic organ of adults. There, hematopoietic stem cells from which all hematopoietic lineages can be generated are preferentially homing. Importantly, bone provides niches for early B cell differentiation and survival of long-lived plasma cells that produced antibodies. Thus, that perturbing bone homeostasis might impact B cell function and antibody production is a highly relevant hypothesis for patients receiving antiresorptive drugs.
We therefore analyzed humoral immune responses of mice treated with ibandronate, a commonly used bisphosphonate. We confirmed the increased bone mass caused by inhibition of osteoclast activity in response to ibandronate and the secondary reduced bone formation due to decreased osteoblast numbers. Thus, bisphosphonate drastically inhibited bone remodeling.
We next analyzed antibodies production by stimulating B cell response with T cell-independent or T cell-dependent immunization in two different setting: i) Ibandronate was injected into mice after a primary immunization in order to mimic common anti-osteoporotic treatments. There, generation of the various B cell populations including bone marrow plasma cells and responses to booster immunization were surprisingly normal. ii) Ibandronate was chronically applied to naïve mice before immunization. Again, responses to immunization appeared normal. However, in that setting, ibandronate drastically shunted plasma cells homing to bone marrow. Interestingly, ibandronate specifically reduced the numbers of megakaryocytes, a known component of the bone marrow plasma cell niche. In line with normal antibody responses, increased plasma cells associated with increased megakaryocyte numbers were then observed in spleens of ibandronate-treated mice.
Thus, inhibiting bone remodeling by ibandronate displaces the bone marrow plasma cell niche toward a compensatory niche by relocating the megakaryocytes to spleen, thereby allowing normal B cell responses. Therefore, we identify megakaryocytes as a key regulator of plasma cell niche plasticity responsive to antiresorptive treatment, and demonstrate that antiresorptive drugs can affect plasma cells homing into bone.
17 May 2014 - 20 May 2014