Bone Hypermineralization Drives Cognitive Rigidity via Osteocyte-Derived Signaling Dysregulation

Hypothesis: Age-related pathological hypermineralization of bone matrix alters osteocyte signaling, reducing the release of carboxylated osteocalcin and increasing sclerostin, which together dampen hippocampal neurogenesis and cortical plasticity, manifesting as cognitive rigidity. Restoring normal osteocyte mechanosensing through intermittent low-magnitude vibration will decrease pathological mineralization, normalize osteocalcin carboxylation, and improve cognitive flexibility in aged mammals.

Mechanistic rationale: In aging bone, hydroxyapatite crystals enlarge and infiltrate osteocyte lacunae and canaliculi, creating a stiff, brittle matrix that impairs fluid shear stress detection by osteocytes [2]. This mechanotransduction deficit lowers intracellular calcium oscillations, leading to reduced transcriptional activity of RUNX2 and decreased vitamin K-dependent gamma-carboxylation of osteocalcin [3][4]. Undercarboxylated osteocalcin accumulates systemically, but its inability to bind hydroxyapatite fails to restrain crystal growth, perpetuating a vicious cycle of hypermineralization. Simultaneously, mechanosensitive osteocytes increase sclerostin secretion, which antagonizes Wnt/beta‑catenin signaling in neural progenitor cells, suppressing hippocampal neurogenesis [5]. The net effect is a brain environment that favors stable, over‑consolidated neural networks—mirroring the seed idea that aging reflects excessive prediction certainty rather than simple decay.

Testable predictions: 1) Aged mice exhibiting elevated lacunar mineralization (quantified by synchrotron FTIR) will show lower levels of carboxylated osteocalcin in serum and higher sclerostin compared with young controls. 2) These mice will perform worse on reversal‑learning tasks (e.g., Morris water maze with platform relocation) indicating cognitive rigidity. 3) Exposing aged mice to 30 Hz, 0.3 g low‑magnitude vibration for 10 min/day, 5 days/week for 8 weeks will reduce lacunar mineralization by ~20 % (via histomorphometry), increase serum carboxylated osteocalcin, decrease sclerostin, and rescue reversal‑learning performance to young‑adult levels. 4) Pharmacologic blockade of osteocyte‑derived sclerostin (using neutralizing antibody) will mimic the cognitive benefits of vibration even without altering mineralization, confirming the signaling pathway.

Falsifiability: If vibration fails to reduce lacunar mineralization or does not alter osteocalcin carboxylation/sclerostin levels, yet cognitive improvement still occurs, the hypothesis that bone matrix changes drive cognitive rigidity via osteocyte signaling is weakened. Conversely, if mineralization improves without cognitive benefit, or if cognitive rescue occurs despite unchanged osteocalcin/sclerostin, alternative mechanisms must be considered. The hypothesis is thus directly testable and falsifiable using established bone histomorphometry, biochemical assays, and behavioral paradigms in aged rodent models.