Unexpected Low Bone Mass Induced by Global Deletion of Keratin 18 But Not Keratin 19 in Mice

Work from our lab has investigated the role of the cytoskeleton in osteoblasts and osteocytes. Our prior work has shown a role for a subset of post-translationally modified tubulin in the osteocyte response to mechanical stimuli and an unexpected role for the type IV intermediate filament protein, synemin, in bone mass acquisition. Indeed, little is known about the role of intermediate filaments in bone. Interestingly, genetic deletion of the most abundant intermediate filament, vimentin, in mice has little effect on bone mass. Here, we demonstrate a role for Keratin 18 in bone physiology. Keratin 18 (gene name Krt18 ) and Keratin 19 (gene name Krt19 ) are both type I intermediate filaments. Heteropolymers of type I (acidic) and type II (basic) intermediate filaments form important cytoskeletal structures. Interestingly, Keratin 18 and Keratin 19 are often found to compensate for one another as they have the capacity to heteropolymerize with the same type II intermediate filament, Keratin 8. Neither Keratin 18 nor Keratin 19’s roles in bone have been previously established. Here, we characterize the impact of the global deletion of Keratin 18 in 13-weeks-old male and female mice in bone and the global deletion of Keratin 19 in 12-weeks-old male mice in bone. Notably, we observed osteopenia in Krt18 but not Krt19 global knockout mice. Using micro computed tomography, we observed significant (p<0.05) osteopenia in Krt18-/- mice (>22% decrease in trabecular BV/TV in males and females and 3% decrease in cortical thickness in females). In contrast, we found no significant osteopenia in Krt19-/- mice. Moving forward, we sought to further characterize the skeletal effects of the absence of Krt18 in bone. Dynamic histomorphometry revealed a significant decrease (p<0.05) in endocortical MS/BS and BFR, suggestive of a role of Keratin 18 in osteoblast function. Ongoing work is examining the cell autonomous effects of Krt18-/- in cultured osteoblasts. Given our earlier work on the cytoskeleton in bone mechano-transduction, we hypothesize that this phenotype may be due to a reduction of mechanosensitivity. Future work will investigate the impacts of Krt18-/- in the anabolic response to bone loading. NIH 5R01AR063631 NIH 5R01AR071614 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.