Lack of Oxygen Encourages FOP Lesions

A major breakthrough in our knowledge of a rare, but debilitating disease is emanating from the Center for Research in FOP and Related Disorders at the Perelman School of Medicine at the University of Pennsylvania. Fibrodysplasia ossificans progressiva (FOP), which impairs movement and breathing, among other things, seems to involve a response to a lack of oxygen. The research team, led by Haitao Wang, Ph.D., a senior research investigator, Robert Pignolo, M.D., Ph.D., an associate professor in the division of Geriatrics and the Ian Cali Distinguished Clinician-Scientist at the Center, and Frederick S. Kaplan, M.D., the Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine and Chief of the division of Molecular Orthopaedic Medicine, published their findings in the Journal of Bone and Mineral Research this month.

Dr. Kaplan told OTW, “It is ironically the lack of oxygen—or more precisely the cellular response to the lack of oxygen that fans the flames of FOP flare-ups (lesions). We found that cells from FOP lesions in humans and in a genetic mouse model of FOP are markedly hypoxic (oxygen starved), that hypoxia triggers a molecular alarm called HIF-1α (pronounced “hif one alpha”), that HIF-1α amplifies bone morphogenetic protein (BMP) signaling in the oxygen starved cells and stimulates heterotopic ossification. Most importantly, by disabling HIF-1α through genetic or pharmacologic means, BMP signaling is restored to normoxic levels in human FOP bone progenitor cells and profoundly reduces heterotopic ossification and resultant disability in a mouse model of FOP.”

As Dr. Kaplan noted in the May 2, 2016 news release, “Hypoxia can occur for many reasons, but in early FOP flare-ups, we speculated that hypoxia might result from the inflammatory microenvironment in lesions. This happens when oxygen supply to the damaged tissue is impaired and oxygen demand by the damaged cells greatly exceeds its supply.”

The news release indicates, “Indeed, every cell continuously produces HIF-1α but rapidly destroys it when the cell has an adequate supply of oxygen. When a cell is oxygen starved, the enzymes that inactivate HIF-1α instantly cease to function, allowing HIF-1α to escape destruction, enter the nucleus of the cell, and trigger an alarm that instructs genes to adapt to a low-oxygen microenvironment. This chain of events allows the cell to survive. The current study showed that HIF-1α inhibitors, specifically the cancer drug imatinib (Gleevec), the natural product apigenin, and the small molecule PX-478, potently inhibit dysregulated BMP signaling induced by HIF-1α in cells, as well as heterotopic ossification following tissue injury in a mouse model of FOP.”

Dr. Kaplan told OTW, “FOP lesions are triggered by inflammation and are intensely hypoxic. Hypoxia activates a cellular alarm called HIF-1α that dramatically amplifies mutant BMP [bone morphogenetic proteins] signaling in FOP and causes explosive heterotopic ossification. Disabling this cellular alarm genetically or pharmacologically restores amplified BMP signaling in FOP stem cells and dramatically reduces heterotopic ossification in a genetic mouse model of FOP. This work provides proof-of-concept that cellular oxygen sensing is a critical regulator of heterotopic ossification in FOP, knowledge that will contribute to the development of more effective treatments for FOP and likely for related common disorders of heterotopic ossification.”