Improvements in bone quality by parathyroid hormone treatment are enhanced in the Nmp4 knockout mouse model

Osteoporosis is linked to increased bone fragility. Unlike anti-resorptive therapies, the analogue of parathyroid hormone, PTH 1-34, is an FDA-approved therapeutic for osteoporosis that enhances bone formation. However, as PTH treatment potency declines over time, it is necessary to investigate the mechanisms involved in this attenuation to reinforce its long-term efficacy. This need has led to investigations into the transcription factor nuclear matrix protein 4 (Nmp4), in which PTH treatment of mice globally lacking Nmp4 (Nmp4^-/-) enhanced bone formation. Yet, the changes in the compositional quality of PTH-stimulated bone in Nmp4^-/- mice are unknown, which in turn could impact the efficiency of this approach. To this end, we characterized cortical bone quality in Nmp4^-/- mice and wild-type littermates treated with PTH for 8 weeks, starting at 16 weeks of age, using micro-computed tomography, Raman spectroscopy, X-ray diffraction, biochemical assays, and biomechanical characterization (whole-bone strength, fracture toughness). PTH treatment and Nmp4 ablation increased tissue and marrow area and maximum moment of inertia. Femora from PTH-treated mice exhibited increased stiffness, maximum load, and fracture resistance. Bone in Nmp4^-/- mice with PTH treatment demonstrated lower mineral crystallinity, decreased mineral-to-matrix ratio, lattice spacing, altered levels of advanced glycation end-products, increased levels of osteocalcin, and increased matrix phosphorylation levels. These results suggest that ablation of Nmp4, in concert with PTH treatment, improved bone function by modulating bone structure and matrix composition. Our findings demonstrate the potential utility of targeting Nmp4 to improve PTH potency and bone quality.