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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 71  |  Issue : 1  |  Page : 18-23

Ossification of calcaneal tendon: Plausible role of hypoxia-induced factor 1 alpha


1 Department of Anatomy, Pandit Deendayal Upadhyaya National Institute for Persons with Physical Disabilities, New Delhi, India
2 Department of Anatomy, NDMC Medical College and Hindu Rao Hospital, New Delhi, India
3 Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
4 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
5 Department of Anatomy, Banaras Hindu University, Banaras, Uttar Pradesh, India

Date of Submission01-Nov-2021
Date of Acceptance03-Nov-2021
Date of Web Publication17-Mar-2022

Correspondence Address:
Dr. Neerja Rani
Department of Anatomy, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jasi.jasi_178_21

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  Abstract 


Introduction: Tendons may rarely be ossified. The calcaneal tendon (CT) is the largest in the body. The incidence and mechanism of ossification of CT is not known. Material and Methods: We carried out a morphological, radiological, histological, and immunohistochemical study on the CT of 50 (30 – male and 20 – female) human cadavers. Results: The mean length (cm) of the CT was 27.60 ± 2.30 (right) and 27.51 ± 2.60 (left) in males and 25.43 ± 0.77 on both sides in females. The contribution to the formation of the CT from the two heads of gastrocnemius muscle was greater from medial head in 84%, lateral head in 12%, and equal in 4%. On screening the CT by C-arm radiography, slight opacification at the site of insertion of CT (bilaterally) was noted in an elderly male. Large, bilateral opacification was seen in another elderly male cadaver. Well-defined lamellar bone with osteocytes lying in lacunae and bone marrow amid the tendon collagenous tissue was noted in hematoxylin- and eosin-stained sections. The osteocytes expressed hypoxia-induced factor 1 alpha. Discussion and Conclusion: In this study, we confirmed that the radiological opacification in the CT was ossification that may have been triggered by hypoxia.

Keywords: Achilles tendon, heterotopic ossification, osteocytes, tendocalcaneum


How to cite this article:
Kaushal P, Roy TS, Jacob TG, Srivastava DN, Sahni C, Rani N. Ossification of calcaneal tendon: Plausible role of hypoxia-induced factor 1 alpha. J Anat Soc India 2022;71:18-23

How to cite this URL:
Kaushal P, Roy TS, Jacob TG, Srivastava DN, Sahni C, Rani N. Ossification of calcaneal tendon: Plausible role of hypoxia-induced factor 1 alpha. J Anat Soc India [serial online] 2022 [cited 2022 Aug 17];71:18-23. Available from: https://www.jasi.org.in/text.asp?2022/71/1/18/339875




  Introduction Top


Tendons are dense, regular connective tissue structures, which transmit force from muscle to bone. They consist of collagen (mostly Type I) and elastin embedded in a proteoglycan-rich matrix. The tendon matrix is produced by the tenoblasts and tenocytes that lie parallel between the longitudinally arranged collagen fibers.[1] Any kind of stress or trauma (both micro and macro) predisposes them to changes in their physicochemical composition.[2] The tendons possess a poor healing capacity owing to their low vascularity and cellularity.[3],[4] Recent studies have identified tendon stem/progenitor cells (TSPCs) in the tendons, which play a crucial role in healing and repair of the tendons, by promoting either tenogenic (into tenocytes) or nontenogenic (into chondrocytes, osteocytes, etc.) differentiation following trauma.[2] However, the factors and the mechanisms regulating them have not been studied in detail.

Tendocalcaneum or Achilles tendon or calcaneal tendon (CT) is the largest in the body and is formed by the union of the aponeuroses of medial and lateral heads of gastrocnemius with the tendon of soleus. This tendon gets inserted onto the posterior surface of the calcaneum. The three muscles are together referred to as triceps surae.[5] CT is the chief plantar flexor of the foot at the ankle joint and mediates powerful heel rise during each gait cycle. Therefore, the CT is subjected to high tensile load of up to 3.9 and 7.7 times of the body weight during walking and running, respectively.[6] These factors make the CT a potential candidate for tendinopathies and degenerative diseases. Calcification, ossification, and decreased oxygen tension have been suggested as the most plausible consequences of degenerative changes in this tendon, and among them, ossification is a rare condition as only sporadic cases have been reported in literature since 1908.[7] Ossification of CT is characterized by the presence of one or more segments of variable-sized ossified mass within the substance of the CT.[8],[9] Its presence is usually asymptomatic but may present as pain or weakness in the tendon, especially during dorsiflexion at the ankle joint.[9] On reviewing the literature, we came across few clinical case reports documenting ossification or calcification in the CT, however, most of them were associated with either previous history of tendon surgery or trauma.[10],[11] Most of the reported sporadic cases included radiological evaluations without histopathological correlations. Further, none of the studies have considered the immunoexpression of plausible factors influencing the ossification of CT in humans. Although the exact mechanism of ossification of CT remains unclear, various factors such as previous surgery for tenotomy,[12] rupture of tendon,[10] correction of club foot,[11] trauma,[12] repetitive microtrauma,[13],[14] degenerative changes,[15] in addition other predisposing conditions such as diabetes mellitus,[16] fluorosis,[17] retinoid therapy,[18] and syphilis[19] have been hypothesized to play a role in ossification of CT. Besides these factors, low vascularity of the CT in the midsection,[4] has been proposed as one of the factors predisposing CT to hypoxia. Hypoxia-induced factor 1 alpha (HIF1α) is one of the key regulators of the cellular and systemic homeostatic response to hypoxia and activates transcription of many genes including those involved in osteogenesis.[7],[20] Since hypoxia is postulated as one of the underlying causes of ossification of CT, therefore we planned to study the immunoexpression of HIF1α in those cases in which we found opacities within the CT during routine human cadaveric dissection and radiological survey of the lower limbs.


  Material and Methods Top


Morphology and morphometry

One hundred (100) CTs from 50 cadavers (30 – male and 20 – female) were studied during routine anatomical dissection.[21] All the cadavers used in the study were donated for teaching and research. Hence, the need for clearance from the Ethics Committee was precluded in this study. Lower limbs with any signs of surgery or injury were excluded from the study. The length of the CT was measured by a standardized measuring tape (with minimum reading of 1 mm). The length of CT was measured from the point of fusion of the muscle bellies of the medial and lateral heads of gastrocnemius up to the calcaneal tubercle. We also noted the contribution made by the two heads of the gastrocnemius based on the extent of the muscle fibers, as described previously.[22] Further, all the tendons were physically examined for the presence of any mass.

Radiology

The tendons with the presence of mass were also screened by a C-arm radiography machine (HF49 DIPIQ, Allengers, India) for the presence of any radiopacities, which was further confirmed by a digital radiography machine (GE Definium XR 656, GE Healthcare, USA).

Histology

The hard mass, identified by these techniques, was excised, fixed in 4% paraformaldehyde, decalcified in 10% solution of ethylenediaminetetraacetic acid, and on completion of decalcification (confirmed by radiograph) was processed for embedding and blocking in paraffin. Hematoxylin and eosin (H and E) staining and immunohistochemistry (IHC) were carried out on 7-μm thick sections of the tissue.

Immunohistochemistry

For IHC, antigen retrieval was done in citrate buffer (pH = 6) at 100°C for 20 min, quenching in 3% hydrogen peroxide followed by blocking in normal goat serum. After overnight incubation in HIF1α primary antibody (bs-07370R Bioss rabbit polyclonal, 1:100) and horseradish peroxidase-tagged secondary antibody (Ultravision Plus Detection System, Thermo Scientific), the expression of HIF1α was visualized by using chromogen diaminobenzidine followed by counterstaining with hematoxylin. The slides were dehydrated, cleared, and mounted with DPX. The slides were examined under the light microscope (Nikon E 600 mounted with DS cooled camera) and photographed. Negative controls were incubated with normal goat serum instead of primary antibody. Two independent observers, unaware of the study, examined the sections for qualitative assessment. These observers commented on individual, high-magnification, digital images of five random fields from both the tissues.

Statistical analysis

The measurements of the tendons were represented as mean ± standard deviation. Paired Student's t-test was used to compare the difference among the right and left limbs of both the sexes. The categorical data of morphometric parameters of males and females were analyzed by the Chi-square test. An overall P < 0.05 was considered statistically significant. All analysis was carried out by Statistical Package for the Social Sciences (SPSS), IBM (International Business Machines), USA.


  Results Top


Morphology and morphometry

The mean length (cm) of the CT in males was 27.60 ± 2.30 (right) and 27.51 ± 2.60 (left), while in the case of females, the corresponding value was 25.43 ± 0.77 for both the limbs. [Table 1] shows the contribution from the medial and lateral heads of gastrocnemius to the formation of CT in both the lower limbs of all the cadavers. However, no statistically significant difference was noted in either of the two parameters studied, between male and female cadavers. Large, bilateral ossification was seen in the CT of a male cadaver (62 years) [Figure 1].
Table 1: The contribution of medial and lateral heads of gastrocnemius to the formation of calcaneal tendon

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Figure 1: Right and left lower limbs showing the ossification in the calcaneal tendon. OCT: Ossified calcaneal tendon, CT: Calcaneal tendon, MG: Medial head of gastrocnemius, LG: Lateral head of gastrocnemius, SN: Sural nerve, SSN: Neuroma in sural nerve, PTA: Posterior tibial artery, PTN: Posterior tibial nerve

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Radiology

While screening the CT of the cadavers with the C-arm, we came across extensive bilateral radiopacities in the CT of one of the male cadavers (62 years) while we encountered slight opacification (bilateral) at the point of insertion of the CT in another male cadaver (59 years). The lateral view X-ray of the lower limbs revealed 6.99-cm long and 7.05-cm long radiopaque masses in the right and left sides, respectively [Figure 2].
Figure 2: Plain radiograph (lateral view) of both lower limbs showing ossification in the right (69.9 mm) and left (70.5 mm) calcaneal tendons

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Histology

Photomicrographs obtained from the H- and E-stained slides revealed the presence of well-defined collagenous fibers with interspersed flattened nuclei. Small empty spaces containing cells with well-defined nuclei were seen lying in between concentric lamellae. Empty space containing some cellular components with clear nucleus and cytoplasm was also noted [Figure 3].
Figure 3: Photomicrographs (×20) showing hematoxylin- and eosin-stained sections obtained from the right and left calcaneal tendons. Note the osteocytes (arrowheads) located in lacunae of the lamellar bone and the bone marrow. Collagen bundles (C) are seen with intervening fibrocyte nuclei (arrows) in the calcaneal tendon

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Immunohistochemistry

The sections that were HIF1α immunostained revealed that HIF1α expression was predominantly localized in the cells lying within the lacunae between the lamellae described above [Figure 4].
Figure 4: Photomicrographs (×20) showing hypoxia-induced factor 1 alpha-immunostained sections obtained from the left and right calcaneal tendons. Note the localization in the osteocytes (arrowheads) located in the lacunae interspersed in the lamellar boneThis is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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  Discussion Top


The results of the present study demonstrated no significant difference in the morphology of the CT of the right and left sides, with a mean length being 27.56 ± 2.47 cm in males and 25.43 ± 0.77 cm in females. The medial head of gastrocnemius contributed more muscle fibers to the formation of CT in majority of the cases. Out of 100 CTs examined radiologically, well-defined opacification was noted in one, while another male cadaver presented a small opacification toward the insertion of the CT. Histological evaluation of the mass revealed features characteristic of ossification, with well-defined concentric lamellae interspersed with lacunae containing osteocytes. Immunoexpression of HIF1α was noted in the cells residing in the lacunae corresponding to osteocytes.

The length of CT was observed ranges between 19 and 27 cm,[22] which corroborates with the findings of the present study. They observed greater contribution by medial head of gastrocnemius (93.3%), while only 6.7% of cases received greater or equal contribution from the lateral head, which was like the pattern observed in the present study [Table 1]. Another study done on 60 cadavers, highlighted the importance of knowledge of variations in the formation of the musculotendinous junction to determine the level of appropriate placement of instruments used in endoscopic recession of gastrocnemius. Further, greater contribution by the medial head of gastrocnemius in majority of the cases points toward the role of these fibers in lateral foot stabilization.[23],[24] These workers, however, did not comment on the presence of ossified mass in any of the 60 cadavers studied. No statistically significant difference in the length of CT (between right and left sides) was noted in a study conducted by Kumar et al. using 64 dissected lower limbs. These investigators have also not commented on the presence of ossification in any of the 64 limbs studied. Acquaintance with the morphologic and morphometric parameters of the CT serves as an important landmark in its anthropometric evaluation and biomechanical characteristics, besides aiding sports physicians and surgeons for the diagnosis and planning treatment for CT injuries, besides being imperative to achieve successful outcomes and minimizing complications while performing either open, minimally invasive, or percutaneous surgery in this region.[25]

First described by 1908, ossification of CT is a rare clinical condition characterized by the occurrence of one or more fragments of variable-sized ossified mass in any part of the substance of the tendon. Plain radiograph has been reported to reliably demonstrate the ossified mass and define the contour of the tendon in majority of the cases.[8] Depending on their anatomical location, radiopaque densities have been classified into three types: type I – at the insertion or superior pole of calcaneum, Type II – 1–3 cm proximal to CT insertion, and Type III – 3–12 cm from the insertion of the tendon. The lesion was further subcategorized based on the degree of ossification as A: partial ossification and B: total ossification of the tendon, respectively.[26] The lower limb observed with extensive ossification in the present study corresponded to Type II with partial ossification while the minor ossification corresponded to Type I. The ossification of the CT may appear as an outgrowth from the periosteum of the calcaneum[19] or the body of the tendon.[15],[19] Although calcification of CT has been reported in various clinical reports,[8],[9],[[10] cases reporting true ossification in tendon are scarce. The two can be differentiated as calcification involves deposition of amorphous calcium phosphate or carbonate, while ossification involves the formation of hydroxyapatite crystals in an observable histological pattern; however, both are indistinguishable in radiographs. Therefore, histological evaluation of the mass excised was carried out and it revealed lamellar bone formation with the presence of lacunae lodging osteocytes and a distinguishable bone marrow cavity [Figure 3].

Ossification of CT has been reported to be twice as common in males,[13] although enlargement of the tendon ossification has been reported with time.[14] Congenital occurrence of ossification of CT cannot be ruled out as Ghormley and John have reported a case of ossification in CT with deficiency of the neural arch of the first sacral segment,[19] although no other study till date has reported congenital ossification of CT. Genetic predisposition of ossified CT was contemplated by Cortbaoui et al. after observing ossified CT in three siblings having no history of trauma, surgery or systemic, metabolic, and infections, however, these investigators did not substantiate their conclusions with any molecular or genetic study.[27] The ossified mass is usually asymptomatic, however, its fracture following trauma may lead to pain.[9],[12] Furthermore, cases associated with either of the predisposing factors must be distinguished from the ones occurring idiopathically. This is important as cases with bilateral ossification of CT with no history of trauma, previous surgery, or metabolic diseases have scarcely been reported in literature.[15],[28] Tamam et al. observed a 1.8 cm × 0.7 cm (left) and 3.2 cm × 2.4 cm (right) sized ossification near the CT insertion of a 41-year-old male patient with no history of direct trauma or previous surgery where the person was involved in extensive physical activity.[15] The radiopaque mass that we observed in the CT measured 6.99 and 7.05 cm, which is one of the largest masses reported in the CT. Small calcific spurs at the insertion site of CT have been reported, especially in healthy individuals, who are physically active, and in patients with rheumatic and articular diseases.[29],[30] Since this study was based on cadaveric dissection, we do not have access to the occupational history and lifestyle of the deceased person.

In the literature, there are limited reports revealing the detailed histology of the ossified CT. Histologic observations of ossified CT have been observed by various workers and they have suggested either of the following patterns of ossification: endochondral or intramembranous ossification, lamellar bone formation, calcified cartilage, and osteoid formation.[10],[14],[31] Hatori et al. observed lamellar bone formation and bone marrow in tendon tissue excised from two patients with ossification in CT. These investigators attributed the ossification to the repetitive microtrauma as the patients provided previous history of heavy manual work. Furthermore, these investigators have documented the presence of both endochondral and intramembranous ossifications in the CT.[14] Majeed et al. observed avascular fibroconnective tissue containing a well-circumscribed nodular area composed of mature cancellous bone along with bony trabeculae separated by vascular spaces in an ossified mass obtained from CT.[31] Development of mature bone following an insult with no inflammatory or degenerative changes in the ossification of CT has been reported.[10] In the present study, we observed well-defined ossification areas with osteocytes lying in the lacunae interspersed between the lamellae of bone [Figure 3].

The exact mechanism of ossification of CT has not been elucidated; however, its ossification has been associated with osteogenesis from circulating osteoblasts, bone growth from injured periosteum, bone formation by fibroblasts or osteoblasts that have originated from fibroblasts[16] or TSPCs, or because of degenerative changes in collagen.[2],[32] Furthermore, vascular pericytes have been reported to possess the capacity to differentiate into both chondrocytes and osteoblasts, thereby permitting them to act as a reservoir of primitive precursor cells giving rise to cells of multiple lineages.[33] Zhang and Wang identified TSPCs as the functional repairing tendon cells and hypothesized malfunction of these cells due to differential expression of various factors may result in tendinopathies. These investigators proposed differentiation of TSPCs into osteoblasts instead of tendon fibroblasts (tenocytes) as the basis of ossification of tendons.[34]

Decrease in the oxygen tension has been reported to play a crucial role in the transformation of tendon into bone. Persistent lowering of the tissue oxygen tension causes transformation of tendon into regions of fibrocartilage in which chondrocytes mediate deposition of calcium at multiple foci.[35] To elucidate the molecular mechanism of heterotopic ossification in the CT, Lin et al. performed Achilles tenotomy in rat. Based on their observations, these investigators proposed endochondral bone formation as the mechanism of ossification in the CT. Furthermore, they also highlighted the role played by hypoxia in chondrogenesis as they noted a significant increase in the mRNA levels of hypoxia-inducible factor HIF1α.[7] This transcriptional regulator has been associated with bone formation by modulating the expression of various downstream genes, especially those mediating adaptive responses.[36] Wang et al. have implicated the role of HIFα in angiogenesis and osteogenesis by elevating the levels of VEGF in osteoblasts of developing bone in mouse models.[37]


  Conclusion Top


Our observations of expression of HIF1α in the osteocytes of ossified CT corroborate the findings of these investigators. It has been postulated that, on sensing decreased oxygen tension, osteoblasts (bone-forming cells) activate the HIFα pathway, which leads to many downstream modifications.[37],[38] Location and mechanism of formation of ossified mass in the CT in this study is also substantiated by the pattern of gross blood supply of CT wherein a watershed zone with limited blood supply in the region 2–6 cm proximal to the insertion of CT has been described.[4] Taken together, the observations of the present study conclude that the radiological opacification in the CT was ossification and HIF1α may be a crucial factor mediating the ossification of the CT.

Acknowledgments

We thank all the body donors and their families who donated their bodies for teaching and research at All India Institute of Medical Sciences, New Delhi. We also thank Mr. Kulwant Singh Kapoor for helping with the statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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