Osteoclasts may play key roles in initiating biomaterial-induced ectopic bone formation

Current studies have identified that biomaterials in the form of sintered calcium phosphate (CaP) ceramics with specific physicochemical properties can induce bone formation in heterotopic sites without additional cells or growth factors, termed osteoinductive biomaterials, which display great potential in repairing large segmental bone defects. However, the underlying mechanism of osteoinduction remains elusive, preventing the optimal design of biomaterials with better osteogenic potential. Recently, accumulative evidence has illustrated that osteoclasts could recruit mesenchymal stem cells (MSCs) and enhance osteogenic differentiation of MSCs by secreting various cytokines, such as collagen triple helix repeat containing 1 (CTHRC1), sphingosine-1-phosphate (S1P), and complement factor 3a (C3a) during bone remodeling. Interestingly, a recent study found that osteoclastogenesis occurred prior to the bone formation during biomaterial-induced ectopic bone formation, and bone formation was blocked once osteoclastogenesis was inhibited with the anti-RANKL antibody at the early stage, which suggest that osteoclasts may play a critical role in the osteoinduction. However, whether osteoclasts could initiate biomaterial-induced ectopic bone formation remains unclear. Consequently, for the first time, we hypothesize that osteoclasts formed in non-osseous environments are perceived as a "starting signal" and osteoclastogenesis is the initiator of biomaterial-induced ectopic bone formation, which may provide useful instruction for osteoinductive materials modification and benefit the development of treatment strategies for heterotopic ossification (HO) in the future.