p38 MAPK inhibitor, FR167653, a potent therapy against PTHrP-induced osteoclastogenesis and bone resorption-related diseases

Parathyroid hormone related protein (PTHrP), was first identified as a causative factor for humoral hypercalcemia of malignancy. Many clinical and experimental studies shows that it regulates endochondral bone development by maintaining the endochondral growth plate at a constant width and contributes to the development and progression of cancer metastasis to bone. Study on mechanism indecates that PTHrP stimulates osteoclastogenesis by increasing receptor activator of NF-kB ligand (RANKL) expression.

     In the previous report, pyridinylimidazole SB203580, a specific inhibitor of p38 MAPK, is used to study p38 MAPK function and the result demonstrates that p38 MAPK is required for osteoclast differentiation [1]. This implies the existence of relationship between p38 MAPK and PTHrP in osteoclastogenesis.
     FR167653 is used to be considered as a potent inhibitor of tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1) production. Recently, FR167653 is confirmed to inhibit the activation of p38 MAPK by suppressing the phosphorylation of p38 MAPK. In their newest paper, Tao et al. found that FR167653 can inhibit osteoclast formation by acting directly on osteoclast precursors cell. Mechanism study of FR167653 on osteoclast formation indicated that the function of FR167653 was achieved by inhibiting expression of c-Fos and NFATc1 in osteoclast precursors. Next, radiographic evidence of bone resorption confirmed that FR167653 reduces PTHrP-induced bone resorption in Vivo[2].
     In conclusion, all the data indicate that p38 MAPK associates with PTHrP in osteoclastogenesis and bone resorptionin. Also, p38 MAPK inhibitor, FR167653 may be a potent agent against PTHrP-induced osteoclastogenesis and bone resorption-related diseases. 

[1]. Endocrinology 2002; 143: 3105–3113
[2]. PLoS ONE 6(8): e23199. doi:10.1371/journal.pone.0023199.