β‐Catenin signaling is important for osteogenesis and hematopoiesis recovery following methotrexate chemotherapy in rats

• Published in: Journal of cellular physiology Vol. 236; no. 5; pp. 3740 - 3751
• Main Authors: Fan, Jian, Su, Yu‐Wen, Hassanshahi, Mohammadhossein, Fan, Chia‐Ming, Peymanfar, Yaser, Piergentili, Alessandro, Del Bello, Fabio, Quaglia, Wilma, Xian, Cory J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-05-2021
• Subjects: Biomedical materials; Bone growth; Bone marrow; Bone resorption; Cancellous bone; Catenin; Cbfa-1 protein; CD34 antigen; Cell differentiation; Cells (biology); Chemotherapy; Differentiation (biology); Hematopoiesis; hematopoietic cells; Hematopoietic stem cells; Methotrexate; Mineralization; Myelosuppression; Osteogenesis; Osteoprotegerin; Progenitor cells; Recovery; Signal transduction; Signaling; Stromal cells; TRANCE protein; Wnt signaling; hematopoietic cells; Wnt signaling; recovery; stromal cells; bone marrow
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30114

Cancer chemotherapy can significantly impair the bone formation and cause myelosuppression; however, their recovery potentials and mechanisms remain unclear. This study investigated the roles of the β‐catenin signaling pathway in bone and bone marrow recovery potentials in rats treated with antimetabolite methotrexate (MTX) (five once‐daily injections, 0.75 mg/kg) with/without β‐catenin inhibitor indocyanine green (ICG)‐001 (oral, 200 mg/kg/day). ICG alone reduced trabecular bone volume and bone marrow cellularity. In MTX‐treated rats, ICG suppressed bone volume recovery on Day 11 after the first MTX injection. ICG exacerbated MTX‐induced decreases on Day 9 osteoblast numbers on bone surfaces, their formation in vitro from bone marrow stromal cells (osteogenic differentiation/mineralization), as well as expression of osteogenesis‐related markers Runx2, Osx, and OCN in bone, and it suppressed their subsequent recoveries on Day 11. On the other hand, ICG did not affect MTX‐induced increased osteoclast density and the level of the osteoclastogenic signal (RANKL/OPG expression ratio) in bone, suggesting that ICG inhibition of β‐catenin does nothing to abate the increased bone resorption induced by MTX. ICG also attenuated bone marrow cellularity recovery on Day 11, which was associated with the suppressed recovery of CD34+ or c‐Kit+ hematopoietic progenitor cell contents. Thus, β‐catenin signaling is important for osteogenesis and hematopoiesis recoveries following MTX chemotherapy.
Acute intense chemotherapy with antimetabolite methotrexate (MTX) causes trabecular bone loss and bone marrow cell depletion, which can recover after chemotherapy in rats. Inhibition of β‐catenin signaling using inhibitor (ICG‐001) suppresses the recovery of trabecular bone volume and bone marrow cellularity following MTX chemotherapy. β‐catenin signaling was important for bone marrow cell osteogenesis and hematopoietic progenitor cell content recovery.