RT Journal Article
SR Electronic
T1 Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.05.936310
DO 10.1101/2020.02.05.936310
A1 Mary Mohrin
A1 Justin Liu
A1 Jose Zavala-Solorio
A1 Sakshi Bhargava
A1 John Maxwell Trumble
A1 Alyssa Brito
A1 Dorothy Hu
A1 Daniel Brooks
A1 Mary L. Bouxsein
A1 Roland Baron
A1 Yuliya Kutskova
A1 Adam Freund
YR 2020
UL http://biorxiv.org/content/early/2020/02/06/2020.02.05.936310.abstract
AB Reducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan.Summary Inhibition of PAPP-A, a regulator of IGF signaling, decreases multi-tissue collagen and extracellular matrix gene expression and modulates mesenchymal stromal cell activity in murine bone marrow.