Therapeutic Potential of Triptolide in Inhibiting Breast Cancer-Induced Bone Destruction -PTHrP as a Therapeutic Target

DI Wu^1,2MingHan Li^2,3ZiNing Huang⁴ChunShi Zhou⁵XiangYu Hu²ZiDong Wang²Gang Wu^2,6,7*

• ¹First Clinical College, Hubei University of Chinese Medicine, Wuhan, China
• ²Affiliated Hospital of Hubei University of Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei Province, China
• ³Acupuncture and Orthopedics College, Hubei University of Chinese Medicine, Wuhan, Hubei Province, China
• ⁴School of Life Sciences, Hubei University, Wuhan, Hubei Province, China
• ⁵School of Sports Medicine, Wuhan Sports University, Wuhan, Hubei Province, China
• ⁶Hubei University of Chinese Medicine, Wuhan, Hubei Province, China
• ⁷Wuhan Sports University, Wuhan, Hubei Province, China

Bone metastases are a common and severe complication in advanced breast cancer, affecting approximately 65% to 70% of patients, and significantly reducing survival time. Osteolytic bone metastases, in particular, are challenging to manage due to their association with skeletal-related events (SREs) that accelerate disease progression and diminish the quality of life. These metastases are driven by a complex interaction between breast cancer cells and the bone microenvironment, leading to increased osteoclast activity and bone destruction. Current treatments, such as bisphosphonates, primarily aim to inhibit osteoclast function but are associated with serious side effects, underscoring the need for alternative therapies. This study investigates Tripterygium wilfordii Hook F. (TwHF), a traditional Chinese medicine, and its bioactive compound Triptolide (TP), as a potential treatment for bone metastases. TP has demonstrated anti-tumor and anti-inflammatory effects, particularly in conditions characterized by abnormal bone remodeling. We studied the effect of TP on mouse bone marrow cells when co-cultured with MDA-MB-231 breast cancer cells or condition media. Our findings suggest that TP inhibits NF-κB and ERK signaling pathways, reduces breast cancer-induced osteoclastogenesis, and decreases RANKL expression in osteoblasts, a key factor in osteoclast differentiation. We for the first time provide evidence for the interaction of parathyroid hormonerelated protein (PTHrP) and TP and propose that TP interfere with PTHrP-mediated signaling, further mitigating osteoclast activity in the tumor microenvironment.