Selective deletion of the membrane-bound isoform of CSF1 in vivo augments the anabolic response to PTH without impairing bone resorption.

Single daily doses of parathyroid hormone (PTH) are an established anabolic therapy for osteoporosis. The actions of PTH in bone are modulated by interactions between osteoblasts and osteoclasts. Colony-stimulating factor 1 (CSF1) exists in both soluble (sCSF1) and membrane-bound (mCSF1) isoforms, with distinct roles in skeletal remodeling identified for each isoform. To investigate the specific role of mCSF1 in PTH-induced bone anabolism, we treated mCSF1 knockout (KO) and wild-type (WT) mice with single daily doses of hPTH (1-34) for 4 weeks. Both genotypes exhibited increased bone mineral density and trabecular bone volume in response to PTH, but KO mice demonstrated significantly greater bone density gains. Histomorphometric analysis demonstrated enhanced osteoblast activity in KO mice, with no significant differences in osteoclast numbers or in the bone resorption marker carboxyterminal cross-linked telopeptide of type 1 collagen (serum CTx), compared to WT. These findings indicate that mCSF1 constrains the anabolic effects of PTH, likely by modulating osteoblast activity, and that its absence enhances bone formation without disrupting resorptive processes. Targeting mCSF1 may therefore represent a strategy to amplify the skeletal benefits of anabolic therapies without impairing bone turnover.