VEGF-D-induced intraosseous lymphangiogenesis drives site-specific heterotopic bone resorption.

Heterotopic ossification (HO) is a debilitating condition that commonly occurs after musculoskeletal injury and is characterized by the formation of bone in soft tissues. Despite advances in understanding its pathogenesis, effective therapies to reverse established heterotopic bone remain lacking. While lymphatic vessels are associated with the destruction of bone in rare diseases such as Gorham-Stout disease, their effect on HO has not been widely explored. Here, we use transgenic mice to determine whether targeted expression of the lymphatic growth factor VEGF-D can promote the therapeutic resorption of bone in a mouse model of HO. We show that control mice lack lymphatic vessels in heterotopic bone. In contrast, Vegfd-overexpressing (Vegfd-OE) mice develop lymphatic vessels in heterotopic bone and form significantly less heterotopic bone than control mice. Additionally, we demonstrate that VEGF-D overexpression or local delivery promotes the therapeutic resorption of established heterotopic bone. Mechanistically, we show that the transition of myeloid cells to osteoclasts and osteoclast-mediated bone resorption are enhanced in Vegfd-OE mice. These findings reveal a previously unrecognized role for lymphatic vessels in regulating heterotopic bone resorption and identify VEGF-D-mediated lymphangiogenesis as a promising therapeutic strategy for HO.