An angiogenic approach to osteoanabolic therapy targeting the SHN3-SLIT3 pathway.

TitleAn angiogenic approach to osteoanabolic therapy targeting the SHN3-SLIT3 pathway.
Publication TypeJournal Article
Year of Publication2023
AuthorsYallowitz AR, Shim J-H, Xu R, Greenblatt MB
Date Published2023 Jul
KeywordsAnimals, Bone and Bones, Cell Differentiation, DNA-Binding Proteins, Endothelial Cells, Membrane Proteins, Mice, Osteoblasts, Osteoclasts, Osteogenesis

Often, disorders of impaired bone formation involve not only a cell intrinsic defect in the ability of osteoblasts to form bone, but moreover a broader dysfunction of the skeletal microenvironment that limits osteoblast activity. Developing approaches to osteoanabolic therapy that not only augment osteoblast activity but moreover correct this microenvironmental dysfunction may enable both more effective osteoanabolic therapies and also addressing a broader set of indications where vasculopathy or other forms microenvironment dysfunction feature prominently. We here review evidence that SHN3 acts as a suppressor of not only the cell intrinsic bone formation activity of osteoblasts, but moreover of the creation of a local osteoanabolic microenvironment. Mice lacking Schnurri3 (SHN3, HIVEP3) display a very robust increase in bone formation, that is due to de-repression of ERK pathway signaling in osteoblasts. In addition to loss of SHN3 augmenting the differentiation and bone formation activity of osteoblasts, loss of SHN3 increases secretion of SLIT3 by osteoblasts, which in a skeletal context acts as an angiogenic factor. Through this angiogenic activity, SLIT3 creates an osteoanabolic microenvironment, and accordingly treatment with SLIT3 can increase bone formation and enhance fracture healing. These features both validate vascular endothelial cells as a therapeutic target for disorders of low bone mass alongside the traditionally targeted osteoblasts and osteoclasts and indicate that targeting the SHN3/SLIT3 pathway provides a new mechanism to induce therapeutic osteoanabolic responses.

Alternate JournalBone
PubMed ID37030497
PubMed Central IDPMC10198948
Grant ListR01 AR075585 / AR / NIAMS NIH HHS / United States
R01 AR078230 / AR / NIAMS NIH HHS / United States
R21 AR077557 / AR / NIAMS NIH HHS / United States
T32 AR071302 / AR / NIAMS NIH HHS / United States
Related Faculty: 
Matthew B. Greenblatt, M.D., Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700