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Deciphering the Role of Lpar4 in Mesenchymal Stem Cell Differentiation

Review of “Lysophosphatidic acid receptor 4 regulates osteogenic and adipogenic differentiation of progenitor cells via inactivation of RhoA/ROCK1/β-catenin signaling” from STEM CELLS by Stuart P. Atkinson

An imbalance in the osteogenic and adipogenic differentiation of human mesenchymal stem cells (MSCs) during normal aging may promote the onset of diseases such as osteoporosis and obesity [1, 2], and so, many have sought to determine the molecular mechanisms controlling the skewed differentiation propensity observed. Studies focusing on lysophosphatidic acid receptors (LPARs) have shown that LPAR1 activation prompts the osteogenesis of human MSCs [3] and inhibits adipose tissue expansion [4, 5], while LPAR4 activation inhibits the osteogenesis of MSCs [3] but inhibits adipose tissue expandability and protection from hepatosteatosis and insulin resistance in a diet‐induced obesity model [6].

Now, researchers from the laboratories of Baoli Wang and Xiaoxia Li (Tianjin Medical University, Tianjin, China) sought to define precisely how Lpar4 regulates adipocytic and osteoblastic differentiation of mouse MSCs in vitro and in vivo, and their new STEM CELLS study now reports a crucial involvement of the ras homolog family member A (RhoA)/Rho‐associated kinases 1 (ROCK1)/β‐catenin signaling pathway [7].

Initial studies conducted by Xie et al. in mouse MSCs in vitro confirmed that Lpar4 overexpression inhibited osteogenic differentiation but boosted adipogenic differentiation and, conversely, that Lpar4 depletion boosted osteogenic differentiation but inhibited adipogenic differentiation. Fascinatingly, subsequent in vivo analyses confirmed this role for Lpar4 - the downregulation of Lpar4 expression via two intratibial injections of small interfering RNA specific for Lpar4 in ten-week-old C57BL/6 mice prompted an increase in osteoblast differentiation and a reduction in fat accumulation within the marrow at one-month post-injection. Overall, these data suggested that Lpar4 may play a crucial role in the development and homeostasis of bone and adipose tissue.

Subsequent mechanistic studies provided evidence that Lpar4 functioned by activating both RhoA/Rock signaling and, through Rock1 activity, Wnt/β‐catenin pathway signaling. To confirm the importance of RhoA/Rock signaling, the team overexpressed Rock1 in MSCs in vitro, finding enhanced osteogenic differentiation and inhibited adipogenic differentiation; furthermore, they also demonstrated that Rock1 overexpression compensated for the loss of osteogenic differentiation observed following Lpar4 overexpression. 

While these data have helped to decipher the roles of Lpar4 expression in MSCs - the regulation of adipocytic and osteogenic differentiation through a novel RhoA/ROCK1/β‐catenin pathway - they also highlight the potential of Lpar4 as a pharmaceutical target in the treatment of metabolic disorders such as osteoporosis and obesity that can arise during the aging process.

For more on Lpar4, MSC differentiation, and potential treatments for metabolic syndromes, stay tuned to the Stem Cells Portal!

References

  1. Pignolo RJ, Ramaswamy G, Fong JT, et al., Progressive osseous heteroplasia: diagnosis, treatment, and prognosis. Application of Clinical Genetics 2015;8:37-48.
  2. Chen Q, Shou P, Zheng C, et al., Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death & Differentiation 2016;23:1128-1139.
  3. Liu Y-B, Kharode Y, Bodine PVN, et al., LPA induces osteoblast differentiation through interplay of two receptors: LPA1 and LPA4. Journal of Cellular Biochemistry 2010;109:794-800.
  4. Simon MF, Daviaud D, Pradère JP, et al., Lysophosphatidic Acid Inhibits Adipocyte Differentiation via Lysophosphatidic Acid 1 Receptor-dependent Down-regulation of Peroxisome Proliferator-activated Receptor γ2. Journal of Biological Chemistry 2005;280:14656-14662.
  5. Rancoule C, Dusaulcy R, Tréguer K, et al., Involvement of autotaxin/lysophosphatidic acid signaling in obesity and impaired glucose homeostasis. Biochimie 2014;96:140-143.
  6. Yanagida K, Igarashi H, Yasuda D, et al., The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity. JCI Insight 2018;3.
  7. Xie Y, Wang X, Wu X, et al., Lysophosphatidic acid receptor 4 regulates osteogenic and adipogenic differentiation of progenitor cells via inactivation of RhoA/ROCK1/β-catenin signaling. STEM CELLS 2020;38:451-463.