Peterson Jonathan R, De La Rosa Sara, Eboda Oluwatobi, Cilwa Katherine E, Agarwal Shailesh, Buchman Steven R, Cederna Paul S, Xi Chuanwu, Morris Michael D, Herndon David N, Xiao Wenzhong, Tompkins Ronald G, Krebsbach Paul H, Wang Stewart C, Levi Benjamin
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, MD 20910, USA.
Sci Transl Med. 2014 Sep 24;6(255):255ra132. doi: 10.1126/scitranslmed.3008810.
Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein-mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3',5'-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury-exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation.
异位骨化（HO）是由于局部或全身性炎症损伤，如烧伤或创伤，导致软组织中异位骨的病理性发育。在HO中，间充质干细胞（MSC）被不适当激活，从而进行成骨分化。通过体外试验和体内研究（跟腱切断术伴背部烫伤）的相关性，我们已经表明，烧伤会增强MSC的成骨潜能，并通过骨形态发生蛋白介导的经典SMAD信号通路导致异位软骨内异位骨形成和功能挛缩。我们进一步证明了一种通过使用腺苷三磷酸双磷酸酶在烧伤部位水解三磷酸腺苷（ATP）来预防HO的策略。烧伤部位的腺苷三磷酸双磷酸酶治疗在体外降低了ATP水平，增加了3',5'-环磷酸腺苷水平，并降低了MSC中SMAD1/5/8的磷酸化水平。这种ATP水解在体内也减少了HO的形成，并减轻了功能障碍。同样，在我们的体内烧伤模型中，用LDN-193189选择性抑制SMAD1/5/8磷酸化可减少HO的形成，并增加损伤部位的活动范围。我们的结果表明，针对烧伤部位ATP水解和SMAD1/5/8磷酸化调节的治疗方法可以治疗烧伤加重的HO形成。
