RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice

Abstract

Edited by Luke O'NeillThe cytokine receptor activator of NFB ligand (RANKL) produced by osteocytes is essential for osteoclast formation in cancellous bone under physiological conditions, and RANKL production by B lymphocytes is required for the bone loss caused by estrogen deficiency. Here, we examined whether RANKL produced by osteocytes is also required for the bone loss caused by estrogen deficiency. Mice lacking RANKL in osteocytes were protected from the increase in osteoclast number and the bone loss caused by ovariectomy. Moreover, these mice did not exhibit the increase in bone marrow B lymphocytes caused by ovariectomy that occurred in control littermates. Deletion of estrogen receptor ␣ from B cells did not alter B cell number or bone mass and did not alter the response to ovariectomy. In addition, lineage-tracing studies demonstrated that B cells do not act as osteoclast progenitors in estrogen-replete or estrogen-deficient mice. Taken together, these results demonstrate that RANKL expressed by osteocytes is required for the bone loss as well as the increase in B cell number caused by estrogen deficiency. Moreover, they suggest that estrogen control of B cell number is indirect via osteocytes and that the increase in bone marrow B cells may be a necessary component of the cascade of events that lead to cancellous bone loss during estrogen deficiency. However, the role of B cells is not to act as osteoclast progenitors but may be to act as osteoclast support cells.

MiR-146a Deletion Protects From Bone Loss in OVX Mice by Suppressing RANKL/OPG and M-CSF in Bone Microenvironment

“…In addition to estrogen‐induced internal differentiation, apoptosis, and the BMM numbers, bone microenvironment, which contains various cytokines between OC and OB communication, plays an important role in osteoclastogenesis. The OC‐positive regulators IL‐6, IL‐1β, TNF‐α, RANKL, and M‐CSF and the negative regulator decoy receptor OPG are produced by bone stromal cells, T and B lymphocytes, and OB . RANKL/OPG ratio is commonly used to measure the ability to promote osteoclastogenesis.…”

Old age causes de novo intracortical bone remodeling and porosity in mice

“…Both of these cytokines enhance RANKLinduced osteoclastogenesis (23,61). Osteocyte-derived RANKL plays an important role in the homeostasis of cortical bone, as evidenced by the fact that conditional deletion of this cytokine in osteocytes increases cortical thickness in young-adult mice and attenuates the cortical thinning caused by estrogen deficiency or glucocorticoid excess (62,63). However, we cannot exclude the possibility that other cells also contribute to the increased sRANKL in marrow of aged murine bone.…”

The Osteocyte Transcriptome Is Extensively Dysregulated in Mouse Models of Osteogenesis Imperfecta

“…In addition, osteocytes play a seminal role in osteoclast generation by virtue of their ability to produce the essential osteoclastogenic factors macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL) as well as osteoprotegerin (OPG). Notably, mice with an osteocyte‐specific deletion of RANKL are resistant to bone loss induced by unloading, ovariectomy, low‐calcium diet, or glucocorticoid excess …”