Lysophosphatidic acid cooperates with 1α,25(OH)2D3 in stimulating human MG63 osteoblast maturation

24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturation

“…LPA has been found to stimulate expression of Fra-2, albeit for rodent fibroblasts, consequent to MEK activation [38]. In our hands we consistently find that the synergistic increase in ALP following co-stimulation with VDR agonists and other factors is always MEK dependent [14,15,18].…”

“…What remains to be determined is whether 24R,25D can promote hOB maturation when co-administered with agents known to synergistically co-operate with 1,25D; it is becoming clear that 1,25D often needs to interact with other factors to prosecute the desired response in target cells [13]. In our hands we consistently find that hOBs do not mobilise alkaline phosphatase (ALP) when treated with 1,25D in a serum-free in vitro setting and will only do so when the cells are in receipt of both 1,25D and certain growth factors such as epidermal growth factor [14], lysophosphatidic acid (LPA) or certain LPA receptor selective agonists [15][16][17][18]. Whilst a significant body of work is emerging on the role of LPA in osteoblast, and indeed skeletal biology in general, we will not expand on those areas here.…”

“…We initially examined the ability of 24R,25D to enhance FHBP-induced maturation in light of our earlier discovery that LPA co-operated with 1,25D in promoting synergistic increases in total ALP activity [15]. The enzyme, which is essential for the synthesis of a mineralised collagen matrix [24], is expressed in greater abundance as hOBs pass from an immature to a more differentiated phenotype.…”

Cytoskeletal reorganisation, 1α,25-dihydroxy vitamin D3 and human MG63 osteoblast maturation

“…Although it is widely recognised that D3 is essential for the provision of a mechanically sound mineralised skeleton the application of D3 to cultured osteoblasts in the absence of serum or selected growth factors does not drive their differentiation. We recently discovered that the principal serum factor co-operating with D3 in promoting human osteoblast maturation is lysophosphatidic acid (Gidley et al, 2006); in isolation D3 was unable to induce osteoblast differentiation but when used in conjunction with human serum a stark, synergistic maturation response occurred. We subsequently found that osteoblast maturation in response to D3 and serum could be blocked by Ki16425, a lysophosphatidic acid (LPA) receptor antagonist (Ohta et al, 2003).…”

“…We subsequently found that osteoblast maturation in response to D3 and serum could be blocked by Ki16425, a lysophosphatidic acid (LPA) receptor antagonist (Ohta et al, 2003). Furthermore the application of commercially available LPA in combination with D3 to MG63 osteoblasts led to striking, synergistic increases in both osteocalcin and alkaline phosphatase (ALP), proteins expressed by the differentiated phenotype (Gidley et al, 2006). Lysophosphatidic acid was identified as the serum borne agent responsible for triggering actin stress fibre accumulation in fibroblasts via activation of Rho (Ridley and Hall, 1992;Ridley and Hall, 1994;Ridley, 2001).…”