Inflammatory Response

Targeting the osteoclastogenic cytokine IL-9 as a novel immunotherapeutic strategy in mitigating inflammatory bone loss in post-menopausal osteoporosis

AUTHORS

Leena Sapra, Chaman Saini, Shivani Sharma, Dibyani Nanda, Aishwarya Nilakhe, Naibedya Chattopadhyay, Avtar Singh Meena, Pradyumna K Mishra, Sarika Gupta, Bhavuk Garg, Vikrant Manhas, Rupesh K Srivastava

ABSTRACT

Recent discoveries have established the pivotal role of IL-9-secreting immune cells in a wide spectrum of inflammatory and autoimmune diseases. However, little is known about how IL-9 contributes to the etiology of inflammatory bone loss in PMO. We observed that IL-9 has a pathological impact on inflammatory bone loss in ovariectomized (Ovx) mice. Our in vivo temporal kinetics analysis revealed that estrogen deprivation enhanced the production of IL-9 from Th cells (majorly Th9 and Th17). Both our ex vivo and in vivo studies corroborated these findings in Ovx mice, as estrogen diminishes the potential of Th9 cells to produce IL-9. Mechanistically, Th9 cells in an IL-9-dependent manner enhance osteoclastogenesis and thus could establish themselves as a novel osteoclastogenic Th cell subset. Therapeutically neutralizing/blocking IL-9 improves bone health by inhibiting the differentiation and function of osteoclasts, Th9, and Th17 cells along with maintaining gut integrity in Ovx mice. Post-menopausal osteoporotic patients have increased IL-9-secreting Th9 cells, which may suggest a potential role for IL-9 in the development of osteoporosis. Collectively, our study identifies IL-9-secreting Th9 cells as a driver of bone loss with attendant modulation of gut-immune-bone axis, which implies IL-9-targeted immunotherapies as a potential strategy for the management and treatment of inflammatory bone loss observed in PMO.

Effect of Single Versus Multiple Fractures on Systemic Bone Loss in Mice

Systemic bone loss after initial fracture contributes to an increased risk of secondary fracture. Clinical research has revealed an association between the risk of future fracture and the number or magnitude of prior fractures. However, the change in systemic bone mass after single versus multiple fractures is unknown. We used ipsilateral femur and tibia fractures as multiple fractures and a femur or tibia fracture as a single fracture to investigate the influence of single versus multiple fractures on systemic bone mass.