Studies of the fate of the osteoclast

Project Summary/Abstract
Osteoporosis is a common disease of aging, caused by a combination of increased osteoclastic (OC) bone
resorption and decreased osteoblastic (OB) bone formation. Low-level chronic inflammation (LLCI),
characterized by increased levels of pro-inflammatory factors induced by activated NF-κB signaling,
contributes to the pathogenesis of age-related osteoporosis by stimulating OC and/or inhibiting OB
differentiation. However, the molecular mechanisms by which LLCI induces bone loss remain incompletely
understood. Our recently published findings indicate that protein levels of TNF receptor associated factor 3
(TRAF3), which negatively regulates NF-κB signaling, are reduced in the bone marrow (BM) of aged mice.
This is because increased amounts of TGFβ released from resorbing bone during aging induce ubiquintin-
mediated degradation of TRAF3 by mesenchymal stromal cells (MSCs). This reduction in TRAF3 levels in
MSCs leads to increased production of the chemokine, SDF1, and subsequent accumulation of a novel subset
of B cell cells (CD19+, B220+ and IgM+) expressing RANKL and CXCR4 (an SDF1 receptor) that we have
identified in the BM during aging. We have called this subset of RANKL+CXCR4+ B cells as RCBs for short.
RCBs directly induce OC formation and produce a soluble factor(s) that inhibits OB differentiation. Importantly,
either plerixafor, a FDA-approved CXCR4 inhibitor, or SM164, an inhibitor of IAP proteins, which prevents
TGFβ1-induced TRAF3 degradation in MSCs, increased trabecular bone mass, associated with reduced
accumulation of RCBs in the BM of aged mice. Our proposed studies will 1) fully characterize RCBs
phenotypically, determine if they are present in humans and if CXCR4 in B cells mediates their accumulation in
the BM of aging mice; 2) determine if TRAF3 expressed by MSCs regulates the accumulation of RCBs in BM
by modulating SDF1 expression; and 3) determine if plerixafor prevents age-related osteoporosis by depleting
RCBs from BM and if targeting it to bone increases its efficacy and reduces adverse effects for the prevention
of age-related osteoporosis. Completion of the proposed studies will determine the mechanisms whereby this
novel set of B cells contributes to bone loss by stimulating bone resorption and inhibiting bone formation
during age-related osteoporosis and importantly, will provide proof of principle that plerixafor or a bone-
targeted formulation of it may be a novel treatment for age-related osteoporosis.

Grant Number: 5R01AR043510-28
NIH Institute/Center: NIH
Principal Investigator: Brendan Boyce