Inhibition Of Heterotopic Ossification Research Articles

Palovarotene Action Against Heterotopic Ossification Includes a Reduction of Local Participating Activin A-Expressing Cell Populations.

Heterotopic ossification (HO) consists of extraskeletal bone formation. One form of HO is acquired and instigated by traumas or surgery, and another form is genetic and characterizes fibrodysplasia ossificans progressiva (FOP). Recently, we and others showed that activin A promotes both acquired and genetic HO, and in previous studies we found that the retinoid agonist palovarotene inhibits both HO forms in mice. Here, we asked whether palovarotene's action against HO may include an interference with endogenous activin A expression and/or function. Using a standard mouse model of acquired HO, we found that activin A and its encoding RNA (Inhba) were prominent in chondrogenic cells within developing HO masses in untreated mice. Single-cell RNAseq (scRNAseq) assays verified that Inhba expression characterized chondroprogenitors and chondrocytes in untreated HO, in addition to its expected expression in inflammatory cells and macrophages. Palovarotene administration (4 mg/kg/d/gavage) caused a sharp inhibition of both HO and amounts of activin A and Inhba transcripts. Bioinformatic analyses of scRNAseq data sets indicated that the drug had reduced interactions and cross-talk among local cell populations. To determine if palovarotene inhibited Inhba expression directly, we assayed primary chondrocyte cultures. Drug treatment inhibited their cartilaginous phenotype but not Inhba expression. Our data reveal that palovarotene markedly reduces the number of local Inhba-expressing HO-forming cell populations. The data broaden the spectrum of HO culprits against which palovarotene acts, accounting for its therapeutic effectiveness. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The Frank Stinchfield Award. Inhibition of heterotopic ossification with radiation therapy in an animal model.

An animal model for the study of heterotopic ossification was developed and the effects of perioperative radiation were analyzed. In Phase I, New Zealand White rabbits (n = 18) underwent surgery either with or without muscle injury on each hip to establish the most reliable model in which to study heterotopic ossification. In Phase II, rabbits (n = 36) underwent either 400, 800, or 1200 cGy radiation to one hip 24 hours after bilateral hip surgery to establish a dose response relationship for postoperative radiation therapy. In Phase III, rabbits (n = 24) underwent preoperative radiation therapy (800 cGy) at 4, 16, or 24 hours preoperatively to investigate the mechanism of action and efficacy of preoperative radiation therapy. Monthly radiographs were graded by blinded observers for severity of heterotopic ossification. Mean grade, intraobserver and interobserver variability, and statistical significance were evaluated. In Phase II, 17 of 18 rabbits generated heterotopic ossification in both hips, and the mean grade of heterotopic ossification was always greater on the operative side with intentional muscle injury. Variability in the grading was considered excellent. Phase II revealed that 800 cGy was the minimal effective dose. Contrary to hypothesis, Phase III revealed an increasing grade of heterotopic ossification coinciding with a decreasing preoperative time interval, with the difference in heterotopic ossification grade with 24-hour versus 4-hour preoperative radiation being significant. The rabbit model is reliable and reproducible and closely resembles the human clinical situation after hip surgery. Preoperative and postoperative radiation effectively prevented heterotopic ossification formation. The results support the use of preoperative radiation and establish a need for additional investigation regarding the mechanism of action and timing of preoperative radiation therapy.