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Saier et al. J Cancer Metastasis Treat 2021;7:43 https://dx.doi.org/10.20517/2394-4722.2021.87 Page 13 of 24

[108]
low affinity to LTB and responds in addition to various eicosanoids . CYSLT has a high affinity for
1
4
CysLTs that is higher for LTD than LTC , whereas CYSLT has a lower overall affinity that is equal for LTC
4
2
4
4
and LTD 4 [109,110] . BLT and CysLT expression is restricted to myeloid cells, whereas BLT and CysLT are
2
1
1
2
expressed in a wide variety of cells [Figure 5].
Role of prostaglandins/leukotrienes in bone cells
Prostaglandins, particularly PGE , are major regulators of bone metabolism. However, their mechanisms of
2
action are complex as they can stimulate both bone resorption and formation and auto-amplify their effects
by inducing COX-2 expression [Figure 6]. In bone, PGE is primarily produced by osteoblasts and
2
contributes indirectly to osteoclastic bone resorption through the upregulation of RANK-L in osteoblasts,
[111]
leading to stimulated osteoclastogenesis and bone resorption . Many cytokines and growth factors known
to potentiate bone resorption, such as IL-1 and IL-6, enhance PGE production by osteoblasts. In contrast,
2
[112]
IL-4 and IL-13 inhibit bone resorption by suppressing PGE production . Analysis of the four EP
2
receptor-deficient mice revealed that PGE stimulates bone resorption in the cultured calvariae through the
2
[113]
EP -cAMP signaling pathway . EP expression on mouse osteoblasts is required for osteoclast
4
4
formation . This suggests that PGE -induced RANK-L expression is mediated through EP [Figure 6]. In
[114]
2
4
addition, PGE , synergistically with RANK-L and M-CSF, directly stimulates the differentiation of mouse
2
osteoclast precursors into osteoclasts through EP and EP , which are downregulated in mature
4
2
osteoclasts [115,116] . This direct effect of PGE on human osteoclasts is however controversial . Paradoxically,
[112]
2
prostaglandins also have inhibitory effects on bone formation. PGE is known to inhibit bone resorption
2
in vitro and increase overall bone mass in vivo . The anabolic effect of PGE is notably mediated by the
[117]
[111]
2
stimulation of osteoblastic differentiation via EP and possibly EP 2 [118] . PGE has also been implicated in
2
4
[112]
several bone-resorptive inflammatory disorders such as osteoarthritis, osteoporosis, and periodontitis .
PGE and COX-2 promote bone formation in response to mechanical loading and endogenous PGE 2
2
[119]
participates in the recovery from osteoporosis and bone fracture .
Global deletion of 5-LOX in mice increases bone mass and protects against bone loss in the ovariectomy
[120]
[121]
-/-
mouse model , although high-fat diet-induced bone loss was increased in 5-LOX mice , suggesting an
interaction between estrogen and leukotriene pathways. Both LTB and LTD , in association with RANK-L,
4
4
promote osteoclast differentiation and bone resorption . Thus, 5-LOX metabolites may also act as
[122]
regulators of bone metabolism. LTB , but not CysLTs, is responsible for Aggregatibacter
4
actinomycetemcomitans-induced bone loss in mice . By promoting osteoclastic bone resorption, LTB
[123]
4
may thereby inhibit bone formation. Osteoclasts express BLT , but not BLT , and produce LTB , suggesting
1
4
2
that LTB /BLT signaling increases osteoclastic activity through autocrine and paracrine pathways . LTB
[112]
4
1
4
[124]
is involved in the induction of pain and bone damage in rheumatoid arthritis . CysLTs also regulate
osteoclast differentiation via CYSLT receptor, supporting the role of CysLT in bone loss [125,126] . Importantly,
1
LTD -CYSLT signaling activates the mitogen-activated protein kinases (MAPK)/extracellular signal-
1
4
regulated kinases (Erk)/c-Jun N-terminal kinase/p38 pathway, which is a key pathway for regulating
osteoclast differentiation and bone resorption. This may explain why the CYSLT antagonist montelukast
1
[127]
inhibits M-CSF- and RANK-L-induced osteoclast differentiation . In addition, montelukast prevents the
association of RANK and TNF receptor associated factor 6 and suppresses reactive oxygen species
generation, which are known to contribute to the pathophysiological development of osteoclastogenesis .
[128]
LTD /CYSLT signaling also plays a role in inducing cellular senescence signaling in osteoblasts, a
1
4
[129]
mechanism that has been described to control bone metastasis . Montelukast also inhibits MMP13
expression in osteoblast, a key factor of proteolytic degradation of membrane-linked RANK-L and
extracellular matrix components . LTD induces chemotaxis and migration of CD34+ bone marrow
[130]
4
progenitors and induces Erk/MAPK signaling in chronic lymphocytic leukemia (CLL) cells, suggesting that
CysLTs may contribute to bone marrow accumulation and homing of CLL cells [131,132] .