Abnormal Bone Growth Research Articles

Heterotopic Ossification After Shoulder Arthroplasty: A Systematic Review.

Shoulder arthroplasty is increasing in incidence over time. One potential complication that is not well studied following shoulder arthroplasty is heterotopic ossification (HO), the abnormal growth of extraskeletal bone in soft tissue. HO has been described as a complication in total hip arthroplasty literature but less described in the setting of shoulder arthroplasty. The aim of this systematic review is to present available evidence regarding the incidence, risk factors, and potential management of HO after shoulder arthroplasty. A systematic search was conducted in June 2023 using Pubmed, Embase, and Ovid Medline databases to retrieve all relevant studies evaluating the occurrence of HO after shoulder arthroplasty. The search was done in duplicate, and a quality assessment of all studies was included. A total of 170 studies were retrieved, of which 6 were included, involving 1,028 patients undergoing shoulder arthroplasty with 1,038 operated shoulders. HO developed postoperatively in 28% of the included shoulders and was symptomatic in 12% with most cases occurring in shoulders that developed osteoarthritis and cuff tear arthropathy. Men appear to have an increased risk of developing HO post shoulder arthroplasty. Fewer than 2% of HO shoulders went on to have revision surgery, and no notable differences were observed in the postoperative mean elevation and external rotation angles of non-HO and HO shoulders. In addition, no reported benefit of the use of nonsteroidal anti-inflammatory drugs was found against the formation of HO after shoulder arthroplasty. HO occurs in 28% of shoulder arthroplasties in our review. Most of these were asymptomatic in the reviewed articles. Male patients and revision surgery with osteoarthritis and cuff tear arthroplasty seem to be at higher risk of developing HO post shoulder arthroplasty. Nonsteroidal anti-inflammatory drugs seem to not prevent the development of HO after shoulder arthroplasty; yet, future studies are needed to verify this claim. Level III; Systematic Review.

Penatalaksanaan Fisioterapi pada Kasus Calcaneus Spur Dextra dengan Modalitas Ultrasound, Hold Rilex dan Calf Raise di RSUD Ciereng Subang

Calcaneus spur is an abnormal bone growth on the inferior part of the os. calcaneus, from the fibrocartilaginous attachment site specifically the plantar fascia ligament, which is a common cause of calcaneus spur. To determine the physiotherapy management in reducing pain, increasing joint range of motion and increasing functional activity ability in Calcaneus Spur Dextra cases with ultrasound, hold rilex and calf raise modalities. After 6 times of therapy using VAS, it shows a decrease in silent pain T1 worth 2 to T6 worth 0, a decrease in motion pain T1 worth 5 to T6 worth 2 and a decrease in tenderness T1 worth 6 to T6 worth 3. Increased active motion LGS in the sagittal plane dextra ankle joint T1: 100- 00- 300 to T6: 200-00-400. Increased functional activity ability which can be seen from the increase in FADI score T1 worth 76% to T6 worth 87% with moderate difficulty. Ultrasound can help reduce pain, hold rilex and calf raise can help increase joint range of motion and improve functional activity ability.

Fibrodysplasia ossificans progressiva: a comprehensive review

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder that causes heterotopic ossification of soft tissues, leading to abnormal bone growth in muscles, tendons, and ligaments. First identified in the 17th century, FOP was classified in 1968 and is linked to a mutation in the Activin A receptor type I gene (ACVR1) which affects bone morphogenetic protein (BMP). The autosomal dominant condition FOP has the potential to lead to aberrant bone development. At birth, FOP individuals appear normal, except for characteristic malformations of the great toes. FOP patients develop painful, inflammatory soft tissue swellings during the first decade of life, often precipitated by soft tissue injury. Minor trauma can trigger new flare-ups and leads to progressive heterotopic ossification. Most FOP sufferers are wheelchair-bound by their third decade and needs lifelong assistance with daily living tasks. Bone morphogenetic proteins (BMPs) are bound by the transmembrane kinase receptor ALK2, which is encoded by the (ACVR1/ALK2 gene). FOPs induce heterotopic bone formation in skeletal muscle and can be caused by mutations in the activin A receptor type I (ACVR1) and activin-like kinase 2 (ALK2) gene. Clinical therapy focuses on preventing and controlling inflammation, with ongoing research focusing on specific therapies targeting receptor activity, aberrant pathways, or cellular components influencing bone neo-formation.

Pharmacologic or genetic targeting of peripheral nerves prevents peri-articular traumatic heterotopic ossification

Heterotopic ossification (HO) is a pathological process that commonly arises following severe polytrauma, characterized by the anomalous differentiation of mesenchymal progenitor cells and resulting in the formation of ectopic bone in non-skeletal tissues. This abnormal bone growth contributes to pain and reduced mobility, especially when adjacent to a joint. Our prior observations suggested an essential role of NGF (Nerve Growth Factor)-responsive TrkA (Tropomyosin Receptor Kinase A)-expressing peripheral nerves in regulating abnormal osteochondral differentiation following tendon injury. Here, we utilized a recently developed mouse model of hip arthroplasty-induced HO to further validate the role of peripheral nerve regulation of traumatic HO. Nerve ingrowth was either modulated using a knockin transgenic animals with point mutation in TrkA, or local treatment with an FDA-approved formulation of long acting Bupivacaine which prevents peripheral nerve growth. Results demonstrate exuberant sensory and sympathetic nerve growth within the peri-articular HO site, and that both methods to reduce local innervation significantly reduced heterotopic bone formation. TrkA inhibition led to a 34% reduction in bone volume, while bupivacaine treatment resulted in a 50% decrease. Mechanistically, alterations in TGFβ and FGF signaling activation accompanied both methods of local denervation, and a shift in macrophages from M1 to M2 phenotypes was observed. In sum, these studies reinforce the observations that peripheral nerves play a role in the etiopathogenesis of HO, and that targeting local nerves represents a potential therapeutic approach for disease prevention.

Disease Activity and Bone Microarchitectural Phenotype in Patients With Axial Spondyloarthritis

Background: Axial spondyloarthritis (AxSpA) is a chronic rheumatic disease characterized by spine inflammation, abnormal bone growth, and paradoxically osteoporosis and vertebral fractures. The pathogenesis of skeletal deficits in this disease is poorly understood. Purpose: We sought to evaluate volumetric bone mineral density (vBMD) and bone microarchitecture in patients with AxSpA and to identify disease-related factors associated with skeletal abnormalities. Methods: We enrolled patients between 2018 and 2021 as part of a 2-year prospective study at a single institution investigating skeletal health and the skeletal effects of interleukin-17 (IL-17) treatment. Patients with AxSpA who met Assessment in SpondyloArthritis International Society (ASAS) classification criteria by X-ray or had evidence of active inflammation on magnetic resonance imaging suggestive of sacroiliitis were referred to the study by their rheumatologists. We excluded those with a history of fragility fracture, multiple myeloma, Cushing’s disease, primary hyperparathyroidism, osteomalacia, untreated vitamin D deficiency, secondary osteoporosis, or other systemic rheumatic diseases, as well as use of oral steroids for 2 or more weeks in the 6 months prior or current use of hormone replacement therapy, current oral bisphosphonate, past or current intravenous bisphosphonate, teriparatide, or denosumab therapies. A total of 1606 patients were screened for eligibility. Of these, 30 participants were enrolled (mean age 43 years, 50% male). Patients with AxSpA had dual-energy X-ray absorptiometry (DXA) measurements of areal BMD (aBMD) and high-resolution peripheral quantitative computed tomography (HR-pQCT) measurements of vBMD microarchitecture and failure load by finite element analysis. Standardized disease assessment tools used included the Bath Ankylosing Spondylitis Disease Activity (BASDAI), Metrology Index (BASMI), and Functional Index (BASFI). Results: In the 30 included patients, mean DXA and HR-pQCT Z-scores were within 1 standard deviation (SD) of normal for all indices, except for total vBMD in males (–1.2 SD below mean). Mean symptom duration was 11.7 years and mean scores for BASDAI, BASFI, and BASMI were 4.6, 3.6, and 2.7, respectively (range 1–10, 10 = severe limitation). Longer disease duration was associated with more severe skeletal deficits at the hip and tibia—specifically, lower hip aBMD, lower meta- and inner-trabecular vBMD, lower trabecular number, and higher trabecular separation and heterogeneity. Conclusion: This study of 30 patients with AxSpA found that abnormalities in bone density and microarchitecture at weightbearing sites were associated with longer disease duration. Because of its small sample size, larger studies are needed to better characterize the pathogenic disease factors that govern skeletal damage in AxSpA.

Hemiepiphysiodesis Corrects Lower Extremity Coronal Plane Deformity in Children with Skeletal Dysplasia Irrespective of Intra-Articular Malalignment

BackgroundSkeletal dysplasias (SkD) are a rare group of disorders characterized by abnormal growth and development of bone and cartilage, often causing limb deformity. Many patients also have ligamentous instability that can accentuate the malalignment. This ligamentous instability can present either a generalized ligamentous laxity or focal coronal plane intra-articular malalignment. Temporary hemiepiphysiodesis (HE) is a commonly employed minimally invasive surgical technique for correcting coronal plane limb deformities. This study evaluated the effectiveness of HE in the correction of knee coronal plane deformity in children with SkD and the correlation of concurrent joint laxity. MethodsA retrospective cohort study was conducted to evaluate radiological outcomes of HE for coronal plane knee deformities in patients with SkD (aged <18 years) who had surgery between January 1, 2008 and December 31, 2020. Changes in distal femoral and proximal tibial mechanical angles, and knee joint line congruence angles (JLCA) prior to HE and at the final follow-up were analyzed. An increased JLCA of ≥±2° was considered a knee with ligamentous instability. Preoperative and postoperative patient-reported pain status was recorded. ResultsFifty-six tibial and 42 femoral HE procedures in 32 children (mean age at HE: 9.8 ± 2.8 years) were included. The deformity was fully corrected in 23/32 (72%) children, at an average annual rate of 6.3° at the distal femur and 3.3° at the proximal tibia, over 21.9 ± 12.6 months. The overall pre-HE JLCA improved by an average of 5.3° (P < .05). The improvement was more pronounced in varus knees (n = 45; P < .05) than valgus knees (n = 12; P = .11) but regardless of the severity of joint instability, pre-HE JLCA did not impede the rate of femoral (r = −0.22) or tibial (r = −0.21) corrections. Preoperative pain was reported by 78% of patients whereas only 25% of patients reported pain postoperatively at the final follow-up (mean follow-up: 26.4 ± 13.5 months). ConclusionsThe presence of coronal plane intra-articular malalignment did not affect the rate and the magnitude of correction with HE in this cohort. Coronal plane deformities and JLCA improve with deformity correction by HE in children with SkD. Key Concepts(1)Intra-articular malalignment at the knee does not impede the success of hemiepiphysiodesis in children with skeletal dysplasia.(2)While all coronal plane knee deformities improved, a more significant improvement was noted in children with varus than valgus.(3)Joint line congruency angles improved with guided growth for coronal plane deformities. Level of EvidenceIII

Melorheostosis (Leri's Disease): A Review.

Melorheostosis is a noncancerous bone disease characterized by abnormal bone and soft tissue growth. Despite being identified almost a century ago, there are still many unknown aspects surrounding this condition. It can often be an incidental discovery, with patients experiencing associated pain and deformities. Diagnosis typically relies on X-rays, although not all cases exhibit the classic candle wax appearance. A new imaging sign known as the "dumpling on a plate sign" has been proposed for flat bones for both MRI and CT scans. A biopsy may be necessary in cases of uncertainty, as there is not a definitive histological feature. It is not uncommon for melorheostosis to be linked with other conditions, and a collaborative approach involving a multidisciplinary team should be considered. This condition should be considered in the differential diagnosis of sclerotic bone conditions. Management is generally aimed at symptom relief, either through conservative measures or surgical intervention.

Post-stapedotomy dizziness after applying topical steroid on footplate: A randomized controlled trial.

Otosclerosis is characterized by abnormal bone growth in the otie capsule. Nowadays, stapedotomy is commonly used for otosclerosis treatment. Currently, postoperative dizziness has been associated with stapedotomy. In 1981, intratympanic dexamethasone was utilized to manage inner ear disorders like tinnitus and acute sensorineural hearing loss. However, there is much uncertainty regarding the effect and safety of topical steroid therapy in the middle ear during stapedotomy. In the present study, we assessed the effect of topical steroid therapy during stapedotomy on postoperative dizziness. Otosclerosis patients eligible for stapedotomy were randomly divided into two groups based on dexamethasone administration or placebo. Audiometric and tympanometry results were observed and recorded for the involved frequencies. The Dizziness Handicap Inventory was used to quantify patient perceptions of dizziness and balance issues. Audiometry and dizziness assessments were repeated at discharge and 4 months after the operation. The study comprised 72 otosclerosis patients undergoing stapedotomy. At discharge, the intervention group showed a significant reduction in the incidence of dizziness compared to the placebo group. However, in the 4-month follow-up after the operation, both groups experienced a decrease in dizziness incidence, with no significant difference between them. There was also no significant difference in audiometric levels between the two groups. Interestingly, the intervention group had a significantly lower need for systemic anti-dizziness drugs after surgery compared to the control group. Topical dexamethasone during stapedotomy effectively minimizes dizziness at discharge and reduces the need for postoperative anti-dizziness medication. 2.

Sistem Pakar Diagnosa Paget's Disease dengan Menerapkan Algoritma Teorema Bayes

Paget's Disease, also known as Paget's Disease of the bone, is a bone disorder that typically arises in the elderly, particularly after the age of 40. The risk of this disease increases with advancing age. Aging and genetic factors are believed to play a role in the development of this condition. Symptoms include bone pain, bone fragility, abnormal bone growth, changes in bone shape, decreased hearing, as well as symptoms such as headaches, dizziness, and joint complaints. Expert systems or artificial intelligence draw inspiration from the knowledge of experts to analyze situations. With algorithms like the Bayes theorem, this system provides solutions to emerging issues. In this context, expert systems aid doctors in identifying diseases without face-to-face consultations. The Bayes theorem serves as the foundation for this mechanism, emulating expert abilities. This research applies the Bayes theorem for an efficient and objective diagnosis of Paget's Disease. The results indicate a strong likelihood of patients having Paget's Disease at 73.87%. Consequently, the use of expert systems has the potential to enhance efficiency and objectivity in handling cases, assisting doctors in formulating diagnoses based on presenting symptoms.

Guided Growth to Treat Anterolateral Tibial Bowing Associated with Congenital Pseudarthrosis of the Tibia.

Anterolateral tibial bowing associated with congenital tibial pseudarthrosis occurs often in patients with neurofibromatosis type 1 and results from the inability of the fractured bone to unite, leading to persistent nonunion, abnormal bone growth, and further bowing of the tibia. Current surgical and nonsurgical approaches demonstrate persistent nonunion or refracture, often resulting in amputation. This report describes the management of 3 patients with anterolateral tibial bowing and NF1 who underwent distal tibia-guided growth. The patients had an average age of 1.6 years at initial operation, with a total of 3 to 4 surgeries over an average of 2.1 years. The latest follow-up on all patients is included, at a mean of 5.1 years after the initial operation. All 3 patients experienced substantial functional improvement and improved alignment of the mechanical axis of the tibia. One patient has experienced refracture. Our study indicates that guided growth can serve as an additional surgical option to improve ALTB and potentially reduce the risk of fracture and pseudarthrosis by restoring normal mechanical alignment. Level-IV, Case Series.

Abstract 688: Radium-223 in combination with darolutamide exhibits synergistic antitumor efficacy in LNCaP prostate cancer models

Abstract Radium-223 dichloride (radium-223) is a targeted alpha therapy that binds to newly formed abnormal bone in bone metastases and induces DNA double-strand breaks (DSBs) in cancer cells, osteoblasts and osteoclasts. Radium-223 is used for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Darolutamide is an androgen receptor inhibitor indicated for patients with metastatic hormone-sensitive prostate cancer or non-metastatic CRPC. We studied the antitumor effects of radium-223 in combination with darolutamide using LNCaP human prostate cancer cells in vitro and an intratibial LNCaP model mimicking prostate cancer metastasized to bone. The in vitro antiproliferative effects of radium-223 and darolutamide were determined using LNCaP cells. Gene set enrichment analysis (GSEA) was conducted on RNA sequencing data from LNCaP cells treated with the synthetic androgen R1881 alone or in combination with darolutamide. LNCaP cells were inoculated into the right tibia of male NOD.scid mice. The mice (n=7-9/group) were randomized based on serum prostate-specific antigen (PSA) and treated with vehicle, radium-223 (330 kBq/kg, Q4Wx2, i.v.), darolutamide (100 mg/kg, BID, p.o.), or with a combination of radium-223 and darolutamide, for 41 days. PSA and the bone turnover markers PINP and CTX-I were measured every second week in serum. Tumor-induced abnormal bone area, bone formation rate and radium-223 uptake in tumor-bearing tibiae were determined by X-ray, histomorphometry and gamma counter, respectively. The combination of radium-223 and darolutamide showed synergistic antiproliferative effects with combination indexes between 0.69-0.75 in vitro. GSEA demonstrated a prominent darolutamide-induced downregulation of DNA damage response (DDR) signaling pathways. In vivo, the combination treatment showed synergistic antitumor efficacy (p=0.04) as demonstrated by lower PSA concentrations when compared with the vehicle, radium-223 or darolutamide monotherapies (p=0.004, p=0.011 and p=0.002, respectively). In the vehicle and combination treatment groups, the mean serum PSA was 541% and 95.9% of the pre-treatment level, respectively. Furthermore, radium-223 alone or in combination with darolutamide inhibited increased bone turnover, tumor-induced abnormal bone growth and trabecular bone formation when compared to vehicle. Concurrent administration of darolutamide did not affect radium-223 uptake in tibiae. Radium-223 in combination with darolutamide exhibited synergistic antitumor efficacy both in vitro and in vivo. The synergistic effects could be due to the radiosensitization of cancer cells by darolutamide-induced downregulation of DDR pathways. Our results suggest that the combination of targeted alpha therapy with an androgen receptor inhibitor is a promising treatment strategy for mCRPC. Citation Format: Christoph A. Schatz, Mari I. Suominen, Andreas Schlicker, Matias Knuuttila, Esa Alhoniemi, Sanna-Maria Käkönen, Bernard Haendler, Urs B. Hagemann, Arne Scholz. Radium-223 in combination with darolutamide exhibits synergistic antitumor efficacy in LNCaP prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 688.

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva.

Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. 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. 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.

The clinical manifestations of hyperostosis frontalis interna: A qualitative systematic review of cases.

Hyperostosis frontalis interna (HFI) is a condition defined as abnormal bone growth on the posterior aspect of the frontal bone. Despite uncertainties regarding its etiology and prognosis, clinicians typically consider HFI a benign pathology. There are no studies organizing all the possible manifestations of the disease. The present study aims to organize all the clinical manifestations of HFI within the current case report/series literature. A blinded PRISMA-guided search of HFI case reports and case series yielded 43 relevant articles and provided 110 patients for analysis. The symptoms presenting alongside HFI were extracted and tabulated. We found high-frequency clinical manifestations of HFI (>20% of patients) to include headaches, obesity, vertigo/dizziness symptoms, cognitive decline, and depression. An additional 15 symptoms were tabulated at frequencies found to be less than 20%. Based on our analysis, we suggest the constellation of high-frequency symptoms can offer a more comprehensive clinical picture of symptomatic HFI which may be valuable to consider for clinicians and future researchers in the field of HFI.

Enhanced BMP signaling in Cathepsin K-positive tendon progenitors induces heterotopic ossification

Heterotopic ossification (HO) is abnormal bone growth in soft tissues that results from injury, trauma, and rare genetic disorders. Bone morphogenetic proteins (BMPs) are critical osteogenic regulators which are involved in HO. However, it remains unclear how BMP signaling interacts with other extracellular stimuli to form HO. To address this question, using the Cre-loxP recombination system in mice, we conditionally expressed the constitutively activated BMP type I receptor ALK2 with a Q207D mutation (Ca-ALK2) in Cathepsin K-Cre labeled tendon progenitors (hereafter “Ca-Alk2:Ctsk-Cre”). Ca-Alk2:Ctsk-Cre mice were viable but they formed spontaneous HO in the Achilles tendon. Histological and molecular marker analysis revealed that HO is formed via endochondral ossification. Ectopic chondrogenesis coincided with enhanced GLI1 production, suggesting that elevated Hedgehog (Hh) signaling is involved in the pathogenesis of HO. Interestingly, focal adhesion kinase, a critical mediator for the mechanotransduction pathway, was also activated in Ca-Alk2:Ctsk-Cre mice. Our findings suggest that enhanced BMP signaling may elevate Hh and mechanotransduction pathways, thereby causing HO in the regions of the Achilles tendon.

A Mechanical Approach to the Growth Plate Behaviour and Chondrocytes Columns Organization

This study aims to explore the behaviour of mechanical stimuli and their effect on growth plate shape under different physiological scenarios and loading conditions. A linear elastic, isotropic, and homogeneous model was implemented to model the epiphyseal progressive ossification and the development of the secondary ossification centre. Results shed light on the role of mechanical stimulus, suggesting that maximum shear stress, hydrostatic stress, and von Mises Stress may contribute to the morphological changes of the growth plate. This model is a useful tool to improve orthopaedic therapies focused on pathologies that imply abnormal bone growth under abnormal mechanical conditions.

Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations.

Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport (IFT) of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3-kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits, and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some misorientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full-length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, which gives rise to a primary skeletal ciliopathy combined with defective motile cilia and PCD.

Defects in Bone and Bone Marrow in Inherited Anemias: the Chicken or the Egg.

Recently, there has been an increasing number of studies on the crosstalk between the bone and the bone marrow and how it pertains to anemia. Here, we discuss four heritable clinical syndromes contrasting those in which anemia affects bone growth and development, with those in which abnormal bone development results in anemia, highlighting the multifaceted interactions between skeletal development and hematopoiesis. Anemia results from both inherited and acquired disorders caused by either impaired production or premature destruction of red blood cells or blood loss. The downstream effects on bone development and growth in patients with anemia often constitute an important part of their clinical condition. We will discuss the interdependence of abnormal bone development and growth and hematopoietic abnormalities, with a focus on the erythroid lineage. To illustrate those points, we selected four heritable anemias that arise from either defective hematopoiesis impacting the skeletal system (the hemoglobinopathies β-thalassemia and sickle cell disease) versus defective osteogenesis resulting in impaired hematopoiesis (osteopetrosis). Finally, we will discuss recent findings in Diamond Blackfan anemia, an intrinsic disorder of both the erythron and the bone. By focusing on four representative hereditary hematopoietic disorders, this complex relationship between bone and blood should lead to new areas of research in the field.

Bilateral plantar and achilles tendon spurs.

Context: A calcaneal spur, also known as an enthesophyte, is an abnormal bone growth on the underside of the calcaneus, which is the most common site for a bone spur to occur. Although there is consensus that calcaneal spurs are a common cause of heel pain, approximately 20% of calcaneal spurs are asymptomatic and their pathology is still not fully understood. Objective: Report the presence of a plantar spur on the calcaneus and another on the insertion of the Achilles tendon bilaterally. Case report: Female patient, 58 years old, housewife, came to our clinic with a history of pain in the heel region bilaterally when walking, more pronounced on the left, which started approximately two years ago. An X-ray of the ankles and feet was requested, where an enthesophyte could be seen at the insertion of the Achilles tendon and in the plantar fascia of the Achilles in both the right and left foot. After diagnosing the presence of enthesophytes, she was medicated with a non-hormonal anti-inflammatory drug and referred to physical therapy. After a year, the pain improved and she returned to his daily walking activities. Conclusion: Conservative clinical treatment produced satisfactory results in the treatment of calcaneal spurs.

Genetic variants and altered expression of SERPINF1 confer disease susceptibility in patients with otosclerosis.

Otosclerosis (OTSC) is a focal and diffuse bone disorder of the human middle ear characterized by abnormal bone growth and deposition at the stapes' footplate. This hinders the transmission of acoustic waves to the inner ear leading to subsequent conductive hearing loss. The plausible convections for the disease are genetic and environmental factors with yet an unraveled root cause. Recently, exome sequencing of European individuals with OTSCrevealed rare pathogenic variants in the Serpin Peptidase Inhibitor, Clade F (SERPINF1)gene. Here, we sought to investigate the causal variants of SERPINF1 in the Indian population. The gene and protein expression was also evaluated in otosclerotic stapes to ameliorate our understanding of the potential effect of this gene in OTSC. A total of 230 OTSC patients and 230 healthy controls were genotyped by single-strand conformational polymorphism and Sanger sequencing methods. Bycomparing the case controls, we identified five rare variants (c.72 C > T, c.151 G > A, c.242 C > G, c.823 A > T, and c.826 T > A) only in patients. Four variants c.390 T > C (p = 0.048), c.440-39 C > T (p = 0.007), c.643 + 9 G > A (p = 0.035), and c.643 + 82 T > C (p = 0.005) were found to be significantly associated with the disease. Down-regulation of SERPINF1 transcript level in otosclerotic stapes was quantified by qRT-PCR, ddPCR and further validated by in situ hybridization. Similarly, reduced protein expression was observed by immunohistochemistry and immunofluorescence in otosclerotic stapes that corroborate with immunoblotting of patients' plasma samples. Our findings identified that SERPINF1 variants are associated with the disease. Furthermore, reduced expression of SERPINF1 in otosclerotic stapes might contribute to OTSC pathophysiology.

Development of an Animal Model for Traumatic Brain Injury Augmentation of Heterotopic Ossification in Response to Local Injury.

Heterotopic ossification (HO) is the abnormal growth of bone in soft connective tissues that occurs as a frequent complication in individuals with traumatic brain injury (TBI) and in rare genetic disorders. Therefore, understanding the mechanisms behind ectopic bone formation in response to TBI is likely to have a significant impact on identification of novel therapeutic targets for HO treatment. In this study, we induced repetitive mild TBI (mTBI) using a weight drop model in mice and then stimulated HO formation via a local injury to the Achilles tendon or fibula. The amount of ectopic bone, as evaluated by micro-CT analyses, was increased by four-fold in the injured leg of mTBI mice compared to control mice. However, there was no evidence of HO formation in the uninjured leg of mTBI mice. Since tissue injury leads to the activation of hypoxia signaling, which is known to promote endochondral ossification, we evaluated the effect of IOX2, a chemical inhibitor of PHD2 and a known inducer of hypoxia signaling on HO development in response to fibular injury. IOX2 treatment increased HO volume by five-fold compared to vehicle. Since pericytes located in the endothelium of microvascular capillaries are known to function as multipotent tissue-resident progenitors, we determined if activation of hypoxia signaling promotes pericyte recruitment at the injury site. We found that markers of pericytes, NG2 and PDGFRβ, were abundantly expressed at the site of injury in IOX2 treated mice. Treatment of pericytes with IOX2 for 72 h stimulated expression of targets of hypoxia signaling (Vegf and Epo), as well as markers of chondrocyte differentiation (Col2α1 and Col10α1). Furthermore, serum collected from TBI mice was more effective in promoting the proliferation and differentiation of pericytes than control mouse serum. In conclusion, our data show that the hypoxic state at the injury site in soft tissues of TBI mice provides an environment leading to increased accumulation and activation of pericytes to form endochondral bone.