Preventing Cartilage Degeneration in Warfighters by Elucidating Novel Mechanisms Regulating Osteocyte-Mediated Perilacunar Bone Remodeling
Technical Report,30 Sep 2015,29 Sep 2016
University of California San Francisco San Francisco United States
Pagination or Media Count:
Our overall hypothesis is that an adverse biologic response to protracted high mechanical loads compromises osteocyte-mediated perilacunar remodeling PLR, bone quality, and cartilage health in post-traumatic osteoarthritis PTOA. Few molecular details are known about the regulation of PLR or bone quality in healthy bone or in disease. Therefore, we will test the hypothesis that mechanical load and TGF signaling interact to regulate PLR, and that this regulation is impaired in,contributes to, and can be targeted for prevention of, the progression of PTOA. We are testing this hypothesis using mouse models and human PTOA tissue. We aim to determine 1 the extent to which mechanical loading regulates PLR in a TGF- dependent manner, 2 the relationship among PLR, strain, TGF, and cartilage degeneration, and 3 the causality of PLR in cartilage degeneration. During the first year, we developed and validated new protocols and reagents. During the second year, we found that PLR is TGF-regulated, which underlies the deregulation of bone quality in mice with altered TGF signaling. Osteocyte-specific deletion of MMP13, a key PLR protease, causes subchondral bone sclerosis as in human PTOA. We also find that PLR is deregulated in human PTOA. We have made great strides in understanding the mechanosensitive regulation of PLR, though a final conclusion requires additional analyses. Since osteocytes have not been implicated in OA, understanding their role in disease has significant potential to yield new drug targets to impede cartilage degeneration.
- Medicine and Medical Research
- Anatomy and Physiology