Accelerated Healing of Traumatic Fractures and Nonunion
Abstract
Traumatic fractures, as experienced by our combat military, not infrequently, promote nonunion. We developed a murine model exhibiting the most rapid and profound systemic increase in bone mass yet observed which holds promise to provide effective strategies to promote non-union healing. Generation of this model entailed mating mice expressing the primate diphtheria toxin receptor (DTR), to those bearing adiponectin (ADQ) Cre (ADQ) (DTRADQ mice). This robust bone formation, which reflects markedly enhanced osteoblast activity, is accompanied by induction of uniquely vigorous osteogenic precursor cells. DTRADQ induction of osteogenesis is caused by bone morphogenetic protein receptor (BMPR) activation likely due to skeletal depletion of its inhibitors gremlin1 (GREM1) and chordin like 1 (CHRDL1). In addition, our data indicate that the poorly defined cells responsible for fracture repair are characterized by expression of the 3.6 kB Col1a promoter. If the mechanistic data in hand are supported by the proposed experiments, there is a reasonable possibility it will eventuate in development of a potent osteogenic drug(s), based upon combined suppression of GREM1 and CHRDL1 and extremely robust osteoprogenitor cells to be transplanted into nonunions. The potent osteogenic drug and osteoprogenitors alone, and particularly in combination, may rapidly promote nonunion healing. Thus, the overarching goal of this proposal is to confirm our mechanistic observations and assess their potential to promote nonunion repair.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2022
- Accession Number
- AD1179182
Entities
People
- Matthew Silva
- Steven Teitelbaum
Organizations
- Washington University in St. Louis