Phospholipase C signaling activated by parathyroid hormone mediates the rapid osteoclastogenesis in the fracture healing of orchiectomized mice

Abstract

Abstract Background The age-related osteoporosis is an increasing risk severely threatening the live quality of aged people. Human parathyroid hormone (hPTH) is applied to the therapy of osteoporosis successfully, however, the mechanism, especially the signaling pathway activated in the healing fracture by PTH is still unknown. Methods The once daily injections of hPTH(1–34) and GR (1–34) (the PLC deficient analog) into the orchiectomized male mice with bone fracture, were started at the second day after fracture and lasted for 4 weeks. To explore the role of phospholipase C signaling in the androgen-deficient fracture healing, the fracture healing were evaluated via radiography, micro-CT, biomechanics testing, serum biochemistry, bone marrow cell culture and gene expression quantification. Results After two weeks of fracture, both peptides significantly increased bone mineral density (BMD), bone mass content (BMC) and bone volume (BV/TV) in the healing area. However, compared to hPTH(1–34), GR(1–34) induced more woven bones, the higher BMC and BMD, as well as the less serum TRAP and osteoclasts. After four weeks of treatment, the effects of hPTH(1–34) on fracture healing showed no difference to those of GR(1–34). Consistently, GR(1–34) induced the similar osteogenesis but less osteoclastogenesis under the ex vivo condition immediately after administration compared to hPTH(1–34), which was verified by the weaker activation of RANKL, NFATC1, TRAP and Cathepsin K in GR(1–34) treatment. Conclusion These results indicated that the PLC signaling activated by the intermittent injection of hPTH(1–34) leads to the bone resorption by rapidly activating the osteoclastogenesis in the fracture healing zone.

Keywords

• Parathyroid hormone
• Fracture healing
• Phopholipase C
• Osteoporosis
• Osteoclastogenesis