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Abstract Context Conventional treatment of X-linked hypophosphatemia (XLH) was reported to prevent dental complications, but whether the preventive effect was different among different types of teeth, including anterior teeth and molar teeth, is uncertain. Evidence of the preventive effect of conventional treatment on ectopic ossifications is also limited. Objective To compare dental complications and ectopic ossifications among adults with XLH with early (<5 years old) or late (≥5 years old) conventional treatment. Methods This retrospective observational study included a total of 30 adults with XLH; orthopantomograms, spinal computed tomography scans, and X-rays of hip/knee joints were studied. Dental complications, including the decayed, missing, filled (DMF) index and devitalized teeth, apical periodontitis, and periodontitis, were evaluated. The ossification of the anterior/posterior longitudinal ligament and yellow ligament indexes (OA/OP/OY indexes) and the sum of the OA/OP/OY indexes (OS index) were utilized to evaluate the severity of spinal ligament ossification. The severity of the hip/knee osteophytes was evaluated using the Kellgren–Lawrence (KL) classification. Results The number of sound teeth was significantly lower and the DMF index was significantly higher in patients with late treatment. The severity of dental complications in the anterior tooth and molar tooth, OA/OP/OY/OS index, and KL grade were not significantly different among patients with early treatment and those with late treatment. Conclusion Early treatment could prevent dental complications but did not prevent ectopic ossification in adult patients with XLH. The difference in the preventive effect was not observed among different types of teeth.

The primary objective of this study was to determine the role of fibroblast growth factor 23 (FGF-23) in the pathogenesis of diffuse idiopathic skeletal hyperostosis (DISH). A total of 61 patients with DISH and 61 age- and sex-matched control patients without DISH were included in this study. The serum FGF-23, creatinine, inorganic phosphate, calcium, albumin, albumin-adjusted calcium and alkaline phosphatase, and C-reactive protein were assessed in both groups. Based on the extent of ossification, DISH group was further divided into T-DISH and L-DISH subgroups. Data were comparatively analyzed between DISH and Non-DISH groups and among T-DISH, L-DISH, and Non-DISH groups, respectively. Besides, the number of ossification segments of all DISH patients was quantified and the correlation between the number of ossification segments and the serum concentration of FGF-23 was analyzed. The results revealed that serum FGF-23 was significantly higher in DISH group than in Non-DISH group, regardless of gender. Interestingly, serum Pi was significantly lower in DISH group than in Non-DISH group. Moreover, a significant difference in serum FGF-23 among T-DISH, L-DISH, and Non-DISH groups was also observed. In contrast to Non-DISH group, both T-DISH and L-DISH subgroups displayed significantly higher serum FGF-23 level. Although the mean value was relatively higher in L-DISH subgroup, no statistically significant difference was found between T-DISH and L-DISH subgroups. In addition, a moderately positive correlation was identified between the number of ossification segments and the serum level of FGF-23. It can be concluded that serum FGF-23 could serve as a positive biomarker for DISH and may play a significant role in ectopic ossification in DISH.

Background This review aims to study the clinical characteristics, diagnostic results, treatments, and outcomes in patients with heterotopic ossification following COVID-19 infection. Methods A literature search for eligible articles was conducted using MEDLINE/Pubmed, Global Health, and Scopus databases (January 12th, 2023), including all case reports and case series from any country and language. The criteria for inclusion in this review were cases of COVID-19 infection subsequently developing heterotopic ossification. Results This systematic review analysed 15 reports ( n  = 20 patients) documenting cases of heterotopic ossification following COVID-19 infection. 80% of the patients were male, with a median age of 59 years. All patients required intensive care unit stay with an average duration of 48.5 days. Mechanical ventilation was necessary for all patients and 30% of them underwent tracheostomy. Common symptoms included stiffness and pain, most frequently affecting multiple locations (70%), with the hips and shoulders being predominantly involved. X-rays were the most commonly used imaging modality, followed by computed tomography. Although treatment was given, some of the patients continued to experience symptoms, particularly stiffness. Conclusion 20 patients who developed heterotopic ossification after COVID-19 have been reported, the majority of which had at least two independent risk factors for this condition. The link between those two clinical entities is therefore uncertain, requiring further investigation. It is nonetheless important to suspect heterotopic ossification in patients with severe COVID-19 infection, prolonged immobilisation, mechanical ventilation, who develop joint pain and stiffness, as this condition can significantly impact patients’ quality of life. Protocol registration CRD42023393516.

IntroductionEctopic ossifications often occur in skeletal muscles or tendons following local trauma or internal hemorrhage, and occasionally cause severe pain that limits activities of daily living. However, mechanisms underlying their development remain unknown.Materials and methodsThe right Achilles tendon in 8-week-old female or male mice was dissected. Some mice were injected intraperitoneally either with phosphate-buffered saline, dimethyl sulfoxide, cimetidine, rapamycin, celecoxib or loxoprofen for 10 weeks. One week after surgery, immunohistochemical analysis was performed for mTOR, TNFα or F4/80. Ten weeks after surgery, ectopic ossification at the tenotomy site was detected by 3D micro-CT. ResultsEctopic ossification was seen at dissection sites in all wild-type mice by dissection of the Achilles tendon. mTOR activation was detected at dissection sites, and development of ectopic ossification was significantly inhibited by administration of rapamycin, an mTOR inhibitor, to wild-type mice. Moreover, administration of the histamine 2 blocker cimetidine, which reportedly inhibits ectopic ossification in tendons, was not effective in inhibiting ectopic ossification in our models. TNFα-expressing F4/80-positive macrophages accumulate at dissection sites and that ectopic ossification of the Achilles tendon dissection was significantly inhibited in TNFα-deficient mice in vivo. Ectopic ossification is significantly inhibited by administration of either celecoxib or loxoprofen, both anti-inflammatory agents, in wild-type mice. mTOR activation by Achilles tendon tenotomy is inhibited in TNFα-deficient mice.ConclusionThe TNFα-mTOR axis could be targeted therapeutically to prevent trauma-induced ectopic ossification in tendons.

Introduction Tendon diseases and injuries are a serious problem for the aged population, often leading to pain, disability and a significant decline in quality of life. The purpose of this study was to determine the influence of aging on biochemistry and histology during tendon healing and to provide a new strategy for improving tendon healing. Method A total of 24 Sprague-Dawley rats were equally divided into a young and an aged group. A rat patellar tendon defect model was used in this study. Tendon samples were collected at weeks 2 and 4, and hematoxylin-eosin, alcian blue and immunofluorescence staining were performed for histological analysis. Meanwhile, reverse transcription-polymerase chain reaction (RT-PCR) and western blot were performed to evaluate the biochemical changes. Results The histological scores in aged rats were significantly lower than those in young rats. At the protein level, collagen synthesis-related markers Col-3, Matrix metalloproteinase-1 and Metallopeptidase Inhibitor 1(TIMP-1) were decreased at week 4 in aged rats compared with those of young rats. Though there was a decrease in the expression of the chondrogenic marker aggrecan at the protein level in aged tendon, the Micro-CT results from weeks 4 samples showed no significant difference( p >0.05) on the ectopic ossification between groups. Moreover, we found more adipocytes accumulated in the aged tendon defect with the Oil Red O staining and at the gene and protein levels the markers related to adipogenic differentiation. Conclusions Our findings indicate that tendon healing is impaired in aged rats and is characterized by a significantly lower histological score, decreased collagen synthesis and more adipocyte accumulation in patellar tendon after repair.

Ossification of the posterior longitudinal ligament (OPLL), a disease characterized by the ectopic ossification of a spinal ligament, promotes neurological disorders associated with spinal canal stenosis. While blocking ectopic ossification is mandatory to prevent OPLL development and progression, the mechanisms underlying the condition remain unknown. Here we show that expression of hydroxyacid oxidase 1 (Hao1), a gene identified in a previous genome-wide association study (GWAS) as an OPLL-associated candidate gene, specifically and significantly decreased in fibroblasts during osteoblast differentiation. We then newly established Hao1-deficient mice by generating Hao1-flox mice and crossing them with CAG-Cre mice to yield global Hao1-knockout (CAG-Cre/Hao1flox/flox; Hao1 KO) animals. Hao1 KO mice were born normally and exhibited no obvious phenotypes, including growth retardation. Moreover, Hao1 KO mice did not exhibit ectopic ossification or calcification. However, urinary levels of some metabolites of the tricarboxylic acid (TCA) cycle were significantly lower in Hao1 KO compared to control mice based on comprehensive metabolomic analysis. Our data indicate that Hao1 loss does not promote ectopic ossification, but rather that Hao1 functions to regulate the TCA cycle in vivo.

Herein, we report the case of a 4-year-old boy, who presented with a cortical lytic lesion of his distal tibia. It was located eccentrically, measured 2 cm in its craniocaudal diameter, and was associated with a lamella-like soft-tissue mineralization that resembled a periosteal reaction. Thus, the lesion’s radiographic features were initially suggestive of an aggressive disease. However, further imaging revealed the lesion to be of cartilaginous origin and to extend into the metaphysis, thus creating the aspect of hyperplastic epiphyseal cartilage. This cartilaginous hyperplasia was likely caused by an ectopic ossification center, although no similar cases have yet been reported. As radiology and clinics no longer indicated the imminent threat of a high-grade malignancy, we decided against a biopsy to avoid interfering with epiphyseal growth. However, because of the unprecedented nature of the given constellation, we closely monitored the lesion radiologically to rule out an untypical manifestation of a benign but potentially expanding lesion, in addition to a growth disturbance resulting from the lesion itself. However, further imaging indicated that mineralization and ossifications, which were already present at the lesion’s initial presentation, increased over time, until the lesion fully disappeared after 13 years of clinical and radiological surveillance. This case is outstanding because of its singular morphology and the long-term follow-up that illustrates its self-limiting natural course. This report provides support in differential diagnosis to help discriminate potentially self-limiting conditions from other diseases that may require invasive diagnosis and/or therapy.

Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk+Scx+ TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling.

The osteoblast differentiation capacity of skeletal stem cells (SSCs) must be tightly regulated, as inadequate bone formation results in low bone mass and skeletal fragility, and over-exuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. RUNX2 is essential for tuning this balance, but the mechanisms of posttranslational control of RUNX2 remain to be fully elucidated. Here, we identify that a CK2/HAUSP pathway is a key regulator of RUNX2 stability, as Casein kinase 2 (CK2) phosphorylates RUNX2, recruiting the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which stabilizes RUNX2 by diverting it away from ubiquitin-dependent proteasomal degradation. This pathway is important for both the commitment of SSCs to osteoprogenitors and their subsequent maturation. This CK2/HAUSP/RUNX2 pathway is also necessary for HO, as its inhibition blocked HO in multiple models. Collectively, active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization. Runx2 is essential for tuning the generation of bone from skeletal stem cells (SSCs). Here, the authors demonstrate that the CK2/HAUSP pathway stabilizes RUNX2 protein thereby regulating the commitment of SSCs to osteoprogenitors as well as their subsequent maturation, and that inhibition of this pathway can block heterotopic ossification.

Diffuse pulmonary ossification (DiPO) is characterised by widespread ectopic bone formation in the lungs. Idiopathic DiPO (I-DiPO) poses significant diagnostic challenges and its ossification mechanism remains unclear. Cicatricial organising pneumonia (CiOP) lesions form fibrous nodules without damaging lung structure. We investigated the histopathological features of I-DiPO, focusing on the surrounding fibrosis, and compared them with those of secondary DiPO (S-DiPO). An analysis was conducted using data from a nationwide DiPO survey in Japan. The dataset included clinical, radiological, and histopathological data of patients with suspected I-DiPO. The specific patterns of ossification and fibrotic findings such as CiOP, organising pneumonia (OP), and subpleural fibrosis were identified. Eighteen and seven patients were classified as having I-DiPO and S-DiPO, respectively. I-DiPO affects younger patients, progresses slowly, commonly occurs in the lower lungs, and has a lower mortality rate. S-DiPO affects older patients, presents with widespread lung lesions, and has a higher mortality rate. CiOP lesions were found in direct continuity with or near ossified lesions in 61.1% and 71.4% of patients with I-DiPO and S-DiPO, respectively. OP, CiOP, and ossified lesions often observed in the same locations in S-DiPO. DiPO has a unique pathogenesis, with an ossification transition occurring via the CiOP lesions. These findings provide valuable insights for future diagnostic approaches and management strategies for this condition.