Accelerated Aging in Cyclophilin B–Deficient Mice Downstream of p21‐Cip1/Waf1

Loss of bone mass and strength is a common problem of advanced age in humans. Defective bone is also a primary finding in osteogenesis imperfecta (OI), a genetic condition most commonly caused by autosomal dominant mutations in the type I collagen genes. Although altered collagen has been proposed to correlate with cellular processes that underlie aging, the causal relationships between them in vivo have not yet been completely explored. Whether aging plays a promoting role in OI development or whether OI contributes to aging, also remains unknown. The PpiB gene encodes cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum required for normal assembly of collagen. Germline deletion or mutations of CypB in mice or humans cause autosomal recessive OI (type IX). Here, we show that mice lacking CypB develop early onset of aging‐associated phenotypes, including kyphosis, fat reduction and weight loss, as well as abnormal teeth, skin, and muscle. Elevated senescence‐associated beta‐galactosidase (SA‐β‐Gal) activity was observed in fat tissues and in bone marrow–derived multipotent stromal cells. Protein levels of the cyclin‐dependent kinase (cdk)‐inhibitor p21‐Cip1/Waf1, a well known senescence marker, were significantly elevated in CypB‐deficient primary cells and mouse tissues. Importantly, loss of p21 in CypB knockout mice attenuated SA‐β‐Gal activity and delayed the development of kyphosis. In addition, less adipose tissue depot and higher SA‐β‐Gal activity were observed in a second OI model, Cola2 ( oim ) mutant mice. A potential upregulation of p21 was also revealed in a limited number of these mice. These findings suggest that some of the features in OI patients may be mediated in part through activation of the p21‐dependent pathway, one of which is closely associated with senescence and aging. This study provides new mechanistic insight into relationships between OI and aging and raises the possibility of using senolytics drugs to treat OI in the future. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.