FKBP5 drives bone marrow stem cells senescence and suppresses osteogenic differentiation via canonical WNT/β-catenin signaling pathway

AUTHORS

Bin Zhu, Bowen Cai, Kaixiao Xue, Guoyong Yin, Shumin Zhou, Jiahu Fang

ABSTRACT

Senile osteoporosis and associated fractures significantly increase the morbidity and mortality of older people, thus increasing the cost of public health. Further investigations are required to explore the molecular causes of senile osteoporosis. In this study, FKBP5 expression in bone marrow mesenchymal stem cells (BMSCs) increased with age, and the degree of expression was inversely related to the patient's bone mineral density or CT values. Functional studies have validated the regulatory function of FKBP5 in BMSCs osteogenesis differentiation through the canonical WNT/β-catenin signaling pathway by binding to β-catenin and promoting its ubiquitination and degradation. Administration of SAFit2, a selective inhibitor of FKBP5, enhanced bone density in an animal model of senile osteoporosis. These findings suggest that FKBP5 may be a novel target and offer a new perspective on osteoporosis treatment.

Peroxiredoxin 5 regulates osteogenic differentiation through interaction with hnRNPK during bone regeneration

AUTHORS

Eunjin Cho, Xiangguo Che, Mary Jasmin Ang, Seongmin Cheon, Jinkyung Lee, Kwang Soo Kim, Chang Hoon Lee, Sang-Yeop Lee, Hee-Young Yang, Changjong Moon, Chungoo Park, Je-Yong Choi, Tae-Hoon Lee

ABSTRACT

Peroxiredoxin 5 (Prdx5) is involved in pathophysiological regulation via the stress-induced cellular response. However, its function in the bone remains largely unknown. Here, we show that Prdx5 is involved in osteoclast and osteoblast differentiation, resulting in osteoporotic phenotypes in Prdx5 knockout (Prdx5Ko) male mice. To investigate the function of Prdx5 in the bone, osteoblasts were analyzed through immunoprecipitation (IP) and liquid chromatography combined with tandem mass spectrometry (LC–MS/MS) methods, while osteoclasts were analyzed through RNA-sequencing. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) was identified as a potential binding partner of Prdx5 during osteoblast differentiation in vitro. Prdx5 acts as a negative regulator of hnRNPK-mediated osteocalcin (Bglap) expression. In addition, transcriptomic analysis revealed that in vitro differentiated osteoclasts from the bone marrow-derived macrophages of Prdx5Ko mice showed enhanced expression of several osteoclast-related genes. These findings indicate that Prdx5 might contribute to the maintenance of bone homeostasis by regulating osteoblast differentiation. This study proposes a new function of Prdx5 in bone remodeling that may be used in developing therapeutic strategies for bone diseases.