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Biomolecules Mar 2024Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. (Review)
Review
BACKGROUND
Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized.
PURPOSE OF REVIEW
This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP.
FUTURE PERSPECTIVES
The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Cell Differentiation; Signal Transduction; Inflammation
PubMed: 38540775
DOI: 10.3390/biom14030357 -
Hand Clinics May 2017Heterotopic ossification (HO) presents a substantial barrier to rehabilitation for patients with severe burns or trauma. Although surgical excision is a mainstay of... (Review)
Review
Heterotopic ossification (HO) presents a substantial barrier to rehabilitation for patients with severe burns or trauma. Although surgical excision is a mainstay of management for this condition, this is unable to address the chronic sequelae of HO, including chronic pain, joint contractures, nerve dysfunction, and open wounds. Current therapeutic modalities are aimed at excision and the prevention of recurrence using nonsteroidal antiinflammatory drugs (NSAIDs) or radiation therapy. Research is now focused on identifying alternative strategies to prevent the initial occurrence of HO through NSAIDs and novel inhibitors of the bone morphogenetic protein signaling pathway.
Topics: Arm Injuries; Burns; Contracture; Elbow Joint; Humans; Joint Dislocations; Ossification, Heterotopic; Range of Motion, Articular
PubMed: 28363301
DOI: 10.1016/j.hcl.2016.12.013 -
FASEB Journal : Official Publication of... Jun 2023Achilles tendon rupture is a common debilitating medical condition. The healing process is slow and can be affected by heterotopic ossification (HO), which occurs when... (Review)
Review
Achilles tendon rupture is a common debilitating medical condition. The healing process is slow and can be affected by heterotopic ossification (HO), which occurs when pathologic bone-like tissue is deposited instead of the soft collagenous tendon tissue. Little is known about the temporal and spatial progression of HO during Achilles tendon healing. In this study we characterize HO deposition, microstructure, and location at different stages of healing in a rat model. We use phase contrast-enhanced synchrotron microtomography, a state-of-the-art technique that allows 3D imaging at high-resolution of soft biological tissues without invasive or time-consuming sample preparation. The results increase our understanding of HO deposition, from the early inflammatory phase of tendon healing, by showing that the deposition is initiated as early as one week after injury in the distal stump and mostly growing on preinjury HO deposits. Later, more deposits form first in the stumps and then all over the tendon callus, merging into large, calcified structures, which occupy up to 10% of the tendon volume. The HOs were characterized by a looser connective trabecular-like structure and a proteoglycan-rich matrix containing chondrocyte-like cells with lacunae. The study shows the potential of 3D imaging at high-resolution by phase-contrast tomography to better understand ossification in healing tendons.
Topics: Animals; Rats; Achilles Tendon; Wound Healing; Osteogenesis; Bone and Bones; Ossification, Heterotopic
PubMed: 37219456
DOI: 10.1096/fj.202201018RRR -
Bone Apr 2018Put most simply, heterotopic ossification (HO) is the abnormal formation of bone at extraskeletal sites. HO can be classified into two main subtypes, genetic and... (Review)
Review
Put most simply, heterotopic ossification (HO) is the abnormal formation of bone at extraskeletal sites. HO can be classified into two main subtypes, genetic and acquired. Acquired HO is a common complication of major connective tissue injury, traumatic central nervous system injury, and surgical interventions, where it can cause significant pain and postoperative disability. A particularly devastating form of HO is manifested in the rare genetic disorder, fibrodysplasia ossificans progressiva (FOP), in which progressive heterotopic bone formation occurs throughout life, resulting in painful and disabling cumulative immobility. While the central role of stem/progenitor cell populations in HO is firmly established, the identity of the offending cell type(s) remains to be conclusively determined, and little is known of the mechanisms that direct these progenitor cells to initiate cartilage and bone formation. In this review, we summarize current knowledge of the cells responsible for acquired HO and FOP, highlighting the strengths and weaknesses of animal models used to interrogate the cellular origins of HO.
Topics: Animals; Disease Models, Animal; Humans; Ossification, Heterotopic; Stem Cells
PubMed: 29409971
DOI: 10.1016/j.bone.2018.01.029 -
Cells Nov 2021Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as... (Review)
Review
Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as -retinoic acid, are produced in the cytoplasm and then interact with nuclear retinoic acid receptors (RARs) to up-regulate the transcription of target genes. The RARs can also interact with target gene response elements in the absence of retinoids and exert a transcriptional repression function. Studies from several labs, including ours, showed that chondrogenic cell differentiation and cartilage maturation require (i) the absence of retinoid signaling and (ii) the repression function by unliganded RARs. These and related insights led to the proposition that synthetic retinoid agonists could thus represent pharmacological agents to inhibit heterotopic ossification (HO), a process that recapitulates developmental skeletogenesis and involves chondrogenesis, cartilage maturation, and endochondral ossification. One form of HO is acquired and is caused by injury, and another severe and often fatal form of it is genetic and occurs in patients with fibrodysplasia ossificans progressiva (FOP). Mouse models of FOP bearing mutant ACVR1R206H, characteristic of most FOP patients, were used to test the ability of the retinoid agonists selective for RARα and RARγ against spontaneous and injury-induced HO. The RARγ agonists were found to be most effective, and one such compound, palovarotene, was selected for testing in FOP patients. The safety and effectiveness data from recent and ongoing phase II and phase III clinical trials support the notion that palovarotene may represent a disease-modifying treatment for patients with FOP. The post hoc analyses showed substantial efficacy but also revealed side effects and complications, including premature growth plate closure in some patients. Skeletally immature patients will need to be carefully weighed in any future regulatory indications of palovarotene as an important therapeutic option in FOP.
Topics: Animals; Chondrogenesis; Clinical Trials as Topic; Humans; Ossification, Heterotopic; Receptors, Retinoic Acid; Retinoids; Signal Transduction
PubMed: 34831466
DOI: 10.3390/cells10113245 -
Stem Cells Translational Medicine Nov 2022Heterotopic ossification (HO) is a dynamic, complex pathologic process that often occurs after severe polytrauma trauma, resulting in an abnormal mesenchymal stem cell...
Heterotopic ossification (HO) is a dynamic, complex pathologic process that often occurs after severe polytrauma trauma, resulting in an abnormal mesenchymal stem cell differentiation leading to ectopic bone growth in soft-tissues including tendons, ligaments, and muscles. The abnormal bone structure and location induce pain and loss of mobility. Recently, we observed that NGF (Nerve growth factor)-responsive TrkA (Tropomyosin receptor kinase A)-expressing nerves invade sites of soft-tissue trauma, and this is a necessary feature for heterotopic bone formation at sites of injury. Here, we assayed the effects of the partial TrkA agonist Gambogic amide (GA) in peritendinous heterotopic bone after extremity trauma. Mice underwent HO induction using the burn/tenotomy model with or without systemic treatment with GA, followed by an examination of the injury site via radiographic imaging, histology, and immunohistochemistry. Single-cell RNA Sequencing confirmed an increase in neurotrophin signaling activity after HO-inducing extremity trauma. Next, TrkA agonism led to injury site hyper-innervation, more brisk expression of cartilage antigens within the injured tendon, and a shift from FGF to TGFβ signaling activity among injury site cells. Nine weeks after injury, this culminated in higher overall levels of heterotopic bone among GA-treated animals. In summary, these studies further link injury site hyper-innervation with increased vascular ingrowth and ultimately heterotopic bone after trauma. In the future, modulation of TrkA signaling may represent a potent means to prevent the trauma-induced heterotopic bone formation and improve tissue regeneration.
Topics: Mice; Animals; Disease Models, Animal; Ossification, Heterotopic; Tenotomy; Burns; Neurons; Osteogenesis
PubMed: 36222619
DOI: 10.1093/stcltm/szac073 -
The Journal of the American Osteopathic... Sep 2018
Topics: Female; Humans; Middle Aged; Ossification, Heterotopic; Temporal Bone; Tomography, X-Ray Computed
PubMed: 30335876
DOI: 10.7556/jaoa.2018.141 -
Journal of the American Veterinary... Nov 2018
Topics: Animals; Bone Diseases, Metabolic; Dog Diseases; Dogs; Ossification, Heterotopic; Skin Diseases, Genetic
PubMed: 30311525
DOI: 10.2460/javma.253.9.1125 -
Scientific Reports Dec 2022Obesity and metabolic disturbances are prevalent in ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF); however,...
Obesity and metabolic disturbances are prevalent in ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF); however, the involvement of dyslipidemia (DL) in OPLL/OLF remains uncertain. We investigated the association between dyslipidemia and OPLL/OLF using a dataset of 458 individuals receiving health screening tests, including computed tomography. Subjects were grouped according to the presence or location of OPLL/OLF: controls (no OPLL/OLF, n = 230), OLF (n = 167), cervical OPLL (n = 28), and thoracic OPLL (n = 33). They were also grouped according to the presence of dyslipidemia (DL[+], n = 215; DL[-], n = 243). The proportion of dyslipidemia in the OLF and OPLL groups was 1.6-2.2 times higher than that in the control group. The proportion of OLF and OPLL in the DL(+) group was significantly higher than that in the DL(-) group (OLF, 43% vs. 29%; cervical OPLL, 14.4% vs. 3.2%; thoracic OPLL, 11.1% vs. 3.7%). Multivariate logistic regression analysis showed an association between all ossification types and dyslipidemia. This study demonstrated an association of dyslipidemia with OPLL/OLF; further investigation on the causal relationship between dyslipidemia and ectopic spinal ligament ossification is warranted to develop a therapeutic intervention for OPLL/OLF.
Topics: Humans; Ligamentum Flavum; Ossification, Heterotopic; Spine; Ossification of Posterior Longitudinal Ligament; Longitudinal Ligaments; Dyslipidemias
PubMed: 36585473
DOI: 10.1038/s41598-022-27136-4 -
Molecular and Cellular Biochemistry Oct 2022Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as... (Review)
Review
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as Activin-like kinase 2 (ALK2), a type I receptor of Bone Morphogenetic Proteins(BMP). Patients with FOP usually undergo episodic flare-ups and the heterotopic ossification in soft and connective tissues. Molecular mechanism study indicates that Activin A, the ligand which normally transduces Transforming Growth Factor Beta signaling, abnormally activates BMP signaling through ALK2 mutants in FOP, leading to heterotopic bone formation. To date, effective therapies to FOP are unavailable. However, significant advances have recently been made in the development of FOP drugs. In this article, we review the recent advances in understanding the FOP mechanism and drug development, with a focus on the small-molecular and antibody drugs currently in the clinical trials for FOP treatment.
Topics: Activins; Bone Morphogenetic Proteins; Drug Development; Humans; Ligands; Mutation; Myositis Ossificans; Ossification, Heterotopic; Transforming Growth Factor beta
PubMed: 35536530
DOI: 10.1007/s11010-022-04446-9