Age-related decline in osteocytic TGFβ signaling disrupts collagen integrity and bone quality

Abstract Poor bone quality (BQ) is a major factor in skeletal fragility in the elderly. Molecular mechanisms establishing and maintaining BQ, independent of bone mass, are unknown but are thought to be primarily determined by osteocytes. We hypothesize that the age-related decline in BQ results from suppression of osteocyte perilacunar/canalicular remodeling (PLR), which maintains bone material properties. We examined bones from young and aged mice with an osteocyte-intrinsic repression of TGFβ signaling (TβRIIocy-/-) that suppresses PLR. Control-aged bone displayed decreased TGFβ signaling and PLR, but aging male TβRIIocy-/- bone did not worsen existing PLR suppression. This epistatic relationship impacted collagen material behavior at the nano and tissue scale in macromechanical tests. The effects of age on bone mass, density, and mineral material behavior were independent of osteocytic TGFβ. We determine that the decline of BQ with age arises from lost osteocyte function and maintenance of collagen integrity in a TGFβ-dependent fashion.