Lysophosphatidic acid receptor 4 regulates osteogenic and adipogenic differentiation of progenitor cells via inactivation of RhoA/ROCK1/β-catenin signaling.

Abstract

Recent evidence revealed that lysophosphatidic acid receptor 4 (LPAR4) plays a role in osteogenesis and bone remodeling in mice. However, the molecular mechanism by which LPAR4 controls osteogenic and adipogenic differentiation of mesenchymal progenitor cells remains pending. In the current study, our data showed that Lpar4 was expressed in bone and adipose tissue and the expression increased during osteoblast and adipocyte differentiation. Lpar4 overexpression in stromal ST2 and preosteoblastic MC3T3-E1 cells inhibited osteogenic differentiation. By contrast, Lpar4 overexpression in ST2 and mesenchymal C3H10T1/2 cells enhanced adipogenic differentiation. Conversely, depletion of endogenous Lpar4 in the progenitor cells induced osteogenic differentiation and inhibited adipogenic differentiation. Furthermore, enhanced osteoblast differentiation and alleviated fat accumulation were observed in marrow of mice after in vivo transfection of Lpar4 siRNA. Mechanism investigations revealed that LPAR4 inhibited the activation of ras homolog family member A (RhoA)/Rho-associated kinases 1 (ROCK1) and canonical Wnt signal pathways. ROCK1 was shown to be able to activate Wnt/β-catenin pathway. We further demonstrated that the overexpression of ROCK1 stimulated osteogenic differentiation and restrained adipogenic differentiation from stromal progenitor cells. Moreover, overexpression of ROCK1 attenuated the inhibition of osteogenic differentiation by LPAR4. The current study has provided evidences demonstrating that RhoA/ROCK1 activates β-catenin signaling to promote osteogenic differentiation and conversely restrain adipogenic differentiation. The inactivation of RhoA/ROCK1/β-catenin signaling is involved in LPAR4 regulation of the directional differentiation of marrow stromal progenitor cells.