Importantly, in the same mouse model, treatment with dexamethasone also inhibited HO formation, suggesting that inflammation pathways, as well as constitutive activation of ALK2 downstream signaling are both required for ectopic bone formation. Recent studies indicate that neurotransmitters are also involved in the process of HO formation. In lesions of patients and mouse HO models, the expression of inflammatory neuropeptides, including substance P and CGRP

were highly up-regulated [28]. Genetic or pharmacologic inhibition of the peptides’ functions successfully selleckchem prevented the BMP-induced HO formation in mouse [28]. Inflammatory neuropeptides are known to be involved in the process Sirolimus molecular weight of bone fracture repair [29] and [30],

suggesting similarity in pathogenesis of HO and fracture healing. Fig. 2 shows therapeutic targets of the current treatments and experimental drugs under development for HO. Current treatment options are effective in preventing HO but the efficacy of these treatments is limited after fibroproliferation and cartilage formation stages. Despite the risk that it can trigger another round of HO, surgery remains the only treatment option to date once bone tissue has formed. Currently, the most popular drugs for HO are cyclo-oxygenase-2 (Cox2) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs), both of which target pro-inflammatory prostaglandins (Fig. 2) [31] and [32]. Traditional NSAIDs such as aspirin, ibuprofen and indomethacin inhibit the formation of both the physiological and inflammatory prostaglandins. The Cox2 inhibitors primarily inhibit the inflammatory prostaglandins and leave the physiological prostaglandins relatively Meloxicam intact [33] and [34]. Studies have shown that lowering inflammatory prostaglandin levels in experimental animals dramatically raises the threshold for HO formation [35]. It is suggested that inflammatory prostaglandins are potent participants along with BMPs in the formation of heterotopic bone [35] and [36]. Cox2 inhibitors and NSAIDs may work by suppressing the

migration and proliferation of inducible mesenchymal cells [37]. In a BMP-demineralized bone matrix induced HO animal model, prostaglandin inhibitors effectively attenuated ectopic bone formation. In contrast, those inhibitors exhibited minimum effect to stop or delay the growth of ectopic bone [36]. These observations suggest that the timing of prostaglandin inhibitor treatment is critical in attenuating HO. Most doctors agree that indomethacin is the best choice among NSAIDs not only to prevent HO, but also to slow down the process of HO development. Their use, however, has been limited because of its adverse drug reaction such as gastrointestinal ulceration, decreased platelet aggregation, and renal toxicity [38].