Heterotopic ossification (HO) consists of ectopic bone formation within soft tissues following surgery or trauma and can have debilitating consequences, but no definitive cure is available. Here we show that HO was essentially prevented in mice receiving nuclear retinoic acid receptor γ (RARγ) agonists. Side effects were minimal, and there was no significant rebound effect. To uncover mechanisms, mesenchymal stem cells were treated with RARγ agonist and transplanted into nude mice. Whereas control cells formed ectopic bone masses, the RARγ agonist-pretreated cells did not, suggesting that they had lost their skeletogenic potentials. Indeed, the cells became unresponsive to rBMP-2 and exhibited reduction of Smad1/5/8 phosphorylation and overall Smad levels. As importantly, the RARγ agonists blocked HO in transgenic mice expressing constitutive-active ALK2Q207D mutant that is related to ALK2R206H found in Fibrodysplasia Ossificans Progressiva patients. The data indicate that the RARγ agonists are potent inhibitors of HO and could also be as effective against congenital HO.

Traumatic brain injury (TBI) involves diffuse axonal injury and induces subtle but persistent changes in brain tissue and function and poses challenges for early detection of neurological injury. The present study uses an automated behavioral analysis system to assess alterations in rodent behavior in the subacute phase in a preclinical mouse model of TBI, controlled cortical impact (CCI) injury. In the first few weeks following CCI, mice demonstrated normal exploratory behaviors and other typical home-cage behaviors. However, beginning 4 weeks post-injury, CCI mice developed disruptions in sleep-wake patterns, including an increased number of awakenings from sleep. Such impaired sleep maintenance was accompanied by an increased latency to reach peak sleep in CCI mice. These sleep disruptions implicate involvement of the thalamocortical network, the activity of which must be tightly regulated to control sleep maintenance. After injury, there was an increase in reactive microglia in thalamic regions as well as delayed reactive astrocytosis that was evident in the thalamic reticular nucleus, which preceded the development of sleep disruptions. These data suggest that cortical injury may trigger inflammatory responses in deeper neuroanatomical structures, including the thalamic reticular nucleus. Such engagement of the thalamus may perturb the thalamocortical network that regulates sleep/awake patterns and contribute to sleep disruptions observed in this model as well as those documented in patients with TBI.

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