P7C3: A novel multi-target therapeutic strategy to combat disuse-related bone loss in space and on earth.

Extended periods of skeletal unloading cause rapid and severe bone loss, structural weakening, and increased fragility. Unlike postmenopausal osteoporosis, disuse bone atrophy is only partially responsive to pharmacological treatments, making it a critical and unresolved medical challenge in both space- and Earth-based medicine. Here, we investigate and assess the dose-response to P7C3 during the transition of bone-derived mesenchymal stem cells to osteoblasts and adipocytes, and its effect during human preosteoclast differentiation into mature osteoclasts in vitro. We further evaluate the in vivo protective properties of P7C3 against pathological bone atrophy induced by mechanical disuse. Data demonstrates that multifunctional P7C3 selectively promoted osteogenesis while inhibiting osteoclast maturation and activity. Proteomic analyses indicate osteogenic augmentation via ↑FSTL-1 and ↓IL-10Rβ, adipogenic inhibition via ↓ADIPOQ and ↑NAMPT, and osteoclastic inhibition via ↓OPN, ↑BMP-7 and ↑OPG. Enrichment analyses suggest the positive regulation of MAPK, JAK/STAT, and Wnt signaling pathways. Transcriptomic data reveal P7C3-induced cell-selective alterations in transcriptional programs within mitochondrial DNA, potentially promoting ATP generation through NADH activity, and regulating cellular energy metabolism. Hindlimb suspension (HLS) induced rapid pathologic bone loss in vivo, with an overarching drive towards adipogenesis (↑C4.A4, ↑FABP3, ↑ADIPOQ, and ↓Dcn) over osteogenesis (↑activin R2A, ↑LIFR and ↓STAT3) and augmented osteoclastic activity and cellular senescence, potentially via MAPK, JAK/STAT, and Wnt signaling. Despite HLS, P7C3 attenuated oxidative stress, RANKL, osteoclastic activity, bone marrow adiposity, cellular senescence, and pathological bone loss. P7C3 presents as an undiscovered and promising multi-target therapeutic strategy against disuse-induced bone atrophy for both space- and Earth-based applications.