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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 3 of 24

Figure 1. Overview of LPA biosynthesis and receptors. Phospholipase A1 or A2 (PLA1 and PLA2) catabolize membrane phospholipids
producing LPA either directly or through the release of LPA precursors (LPC, LPE, and LPS) that are metabolized in LPA by autotaxin
(ATX) due to its lysophospholipase D activity. LPA activates six specific G protein-coupled receptors (LPA ). LPC:
1-6
Lysophosphatidylcholine; LPE: lysophosphatidylethanolamine; LPS: lysophosphatidylserine; LPA: lysophosphatidic acid.

extracellular nucleotides are rare.

LPA activates a series of six different G-protein coupled receptors (LPA ). Overall, LPA receptors link to all
1-6
, but, due to specific interactions,
types of heterotrimeric G proteins, G a12/13 , G aq/11 , G ai/o , and G as
LPA receptors can have redundant, synergic, or opposite actions. LPA is the most ubiquitous LPA
1
receptor in adults, with prevalence in brain, heart, testis, ovary, prostate, colon, thymus, and pancreas.
Eukaryotic cells frequently express multiple LPA receptors. Mature osteoclasts express LPA , LPA , LPA ,
2
4
1
LPA , and LPA , whereas osteoblasts express mostly LPA and LPA and traces of LPA . As a marked
[17]
[16]
1
4
5
6
5
specificity, LPA is the sole LPA receptor whose mutation is involved in a human pathology of
6
congenital alopecia . The impact of LPA mutation on bone homeostasis has not been reported yet.
[18]
6
Role of LPA on bone cells
LPA is produced at the bone site, as we previously showed in the context of bone metastasis [Figure 2].
Through its action on both cancer cells and osteoclasts, LPA promotes the progression of osteolytic
lesions . LPA plays a key role during bone development. However, origin of LPA in bone is still
[19]
[20]
[13]
incompletely understood, although adipocytes and osteoblasts are potential sources that may account
for bone homeostasis and bone metastasis. Lpar1 mice revealed growth retardation due multiple alteration
-/-
at levels of both the central nervous and the musculoskeletal systems, including inhibition of chondrocyte
proliferation, defects in endochondral ossification, and a low bone mass phenotype linked to decreased