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2016 ; 7
(ä): 375
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Wedelolactone Enhances Osteoblastogenesis but Inhibits Osteoclastogenesis through
Sema3A/NRP1/PlexinA1 Pathway
#MMPMID27803667
Liu YQ
; Han XF
; Bo JX
; Ma HP
Front Pharmacol
2016[]; 7
(ä): 375
PMID27803667
show ga
Bone remodeling balance is maintained by tight coupling of osteoblast-mediated
bone formation and osteoclast-mediated bone resorption. Thus, agents with the
capacity to regulate osteoblastogenesis and osteoclastogenesis have been
investigated for therapy of bone-related diseases such as osteoporosis. In this
study, we found that wedelolactone, a compound isolated from Ecliptae herba, and
a 9-day incubation fraction of conditioned media obtained from
wedelolactone-treated bone marrow mesenchymal stem cell (BMSC) significantly
inhibited tartrate-resistant acid phosphatase (TRAP) activity in RANKL-stimulated
osteoclastic RAW264.7 cells. Addition of the semaphorin 3A (Sema3A) antibody to
the conditioned media partially blocked the medium's inhibitory effects on the
RAW264.7 cells. In BMSC, mRNA expression of Sema3A increased in the presence of
different wedelolactone concentrations. Blocking Sema3A activity with its
antibody reversed wedelolactone-induced alkaline phosphatase activity in BMSC and
concurrently enhanced wedelolactone-reduced TRAP activity in osteoclastic
RAW264.7 cells. Moreover, in BMSC, wedelolactone enhanced binding of Sema3A with
cell-surface receptors, including neuropilin (NRP)1 and plexinA1. Furthermore,
nuclear accumulation of ?-catenin, a transcription factor acting downstream of
wedelolactone-induced Sema3A signaling, was blocked by the Sema3A antibody. In
osteoclastic RAW264.7 cells, conditioned media and wedelolactone promoted the
formation of plexin A1-NRP1, but conditioned media also caused the sequestration
of the plexin A1-DNAX-activating protein 12 (DAP12) complex and suppressed the
phosphorylation of phospholipase C (PLC)?2. These data suggest that wedelolactone
promoted osteoblastogenesis through production of Sema3A, thus inducing the
formation of a Sema3A-plexinA1-Nrp1 complex and ?-catenin activation. In
osteoclastic RAW264.7 cells, wedelolactone inhibited osteoclastogenesis through
sequestration of the plexinA1-DAP12 complex, induced the formation of
plexinA1-Nrp1 complex, and suppressed PLC?2 activation.