FGF9 has complex and important roles in skeletal development and repair. We have previously observed that Fgf9 expression in osteoblasts (OBs) is regulated by G protein signaling and therefore the present study was done to determine whether OB-derived FGF9 was important in skeletal homeostasis. To directly test this idea, we deleted functional expression of Fgf9 gene in OBs using a 2.3kb collagen type I promoter-driven Cre transgenic mouse line (Fgf9). Both Fgf9 knockout (Fgf9) and the Fgf9 floxed littermates (Fgf9) mice were fully backcrossed and maintained in an FBV/N background. Three month old Fgf9 mice displayed a significant decrease in cancellous bone and bone formation in the distal femur and a significant decrease in cortical thickness at the TFJ. Strikingly, female Fgf9 mice did not display altered bone mass. Continuous treatment of mouse BMSCs with exogenous FGF9 inhibited mouse BMSC mineralization while acute treatment increased the proliferation of progenitors, an effect requiring the activation of Akt1. Our results suggest that mature OBs are an important source of FGF9, positively regulating skeletal homeostasis in male mice. Osteoblast-derived FGF9 may serve a paracrine role to maintain the osteogenic progenitor cell population through activation of Akt signaling.

Progranulin (PGRN) is best known as a glial protein for which deficiency leads to the most common inherited form of frontotemporal dementia. Recently, PGRN has been found to be an adipokine associated with diet-induced obesity and insulin resistance. Therefore, PGRN may have homeostatic effects on bone because PGRN is reported to promote the differentiation of bone-resorbing osteoclasts. We investigated the actions of PGRN on bone using PGRN gene (Grn) knockout (KO) mice and transgenic mice with PGRN mutation and surprisingly found that loss of PGRN prevented the bone loss in female mice induced by aging and estrogen deficiency, whereas it had no effect on male bones during aging. Strikingly, bone formation was increased in female (but not male) PGRN KO mice. We also found that loss of PGRN inhibited bone resorption and osteoclastogenesis in both male and female mice and promoted the production of osteogenic factors in osteoclast lineage cells. These results indicate that PGRN serves to uncouple bone turnover in female mice by promoting bone resorption and suppressing bone formation. Furthermore, we demonstrated that microglial cells/macrophages, but not adipocytes, are an important source of PGRN in producing negative skeletal effects in females. Targeting PGRN production by microglial cells/macrophage-lineage cells may provide a therapeutic approach for the treatment of osteoporosis in females.