PRMT5 is necessary to form distinct cartilage identities in the knee and long bone.

During skeletal development, limb progenitors become specified as chondrocytes and subsequently differentiate into specialized cartilage compartments. We previously showed that the arginine dimethyl transferase, PRMT5, is essential for regulating the specification of progenitor cells into chondrocytes within early limb buds. Here, we report that PRMT5 regulates the survival of a separate progenitor domain that gives rise to the patella. Independent of its role in knee development, PRMT5 regulates several distinct types of chondrocyte differentiation within the long bones. Chondrocytes lacking PRMT5 have a striking blockage in hypertrophic chondrocyte differentiation and are marked by abnormal gene expression. PRMT5 remains important for articular cartilage and hypertrophic cell identity during adult stages, indicating an ongoing role in homeostasis of these tissues. We conclude that PRMT5 is required for distinct steps of early and late chondrogenic specialization and is thus a critical component of multiple aspects of long bone development and maintenance.

Common cellular origin and diverging developmental programs for different sesamoid bones.

Sesamoid bones are small auxiliary bones that form near joints and contribute to their stability and function. Thus far, providing a comprehensive developmental model or classification system for this highly diverse group of bones has been challenging. Here, we compare our previously reported mechanisms of patella development in the mouse with those of two anatomically different sesamoids, namely lateral fabella and digit sesamoids. We show that all three types of sesamoid bones originate from Sox9+ /Scx+ progenitors under the regulation of TGFß and independently of mechanical stimuli from muscles. Whereas BMP2 regulates the growth of all examined sesamoids, the differentiation of lateral fabella or digit sesamoids is regulated redundantly by BMP4 and BMP2. Next, we show that whereas patella and digit sesamoids initially form in juxtaposition to long bones, lateral fabella forms independently and at a distance. Finally, our evidence suggests that, unlike the synovial joint that separates patella from femur, digit sesamoids detach from the phalanx by formation of a fibrocartilaginous joint. These findings highlight both common and divergent molecular and mechanical features of sesamoid bone development, which underscores their evolutionary plasticity.

Genetics of the patella.

We review genetic diseases with identified molecular bases that include abnormal, reduced (hypoplasia), or absent (aplasia) patellae as a significant aspect of the phenotype. The known causal genes can be broadly organized according to three major developmental and cellular processes, although some genes may act in more than one of these: limb specification and pattern formation; DNA replication and chromatin structure; bone development and differentiation. There are also several genes whose phenotypes in mice indicate relevance to patellar development, for which human equivalent syndromes have not been reported. Developmental studies in mouse and chick embryos, as well as patellar involvement in human diseases with decreased mobility, document the additional importance of local environmental factors in patellar ontogenesis. Patellar anomalies found in humans can be an important clue to a clinical genetic diagnosis, and a better knowledge of the genetics of patellar anomalies will improve our understanding of limb development.

Computational model for the patella onset.

The patella is a sesamoid bone embedded within the quadriceps tendon and the patellar tendon that articulates with the femur. However, how is it formed is still unknown. Therefore, here we have evaluated, computationally, how three theories explain, independently, the patella onset. The first theory was proposed recently, in 2015. This theory suggested that the patella is initially formed as a bone eminence, attached to the anterodistal surface of the femur, while the quadriceps tendon is forming. Thereafter, a joint develops between the eminence and the femur, regulated by mechanical load. We evaluated this theory by simulating the biochemical environment that surrounds the tendon development. As a result, we obtained a patella-like structure embedded within the tendon, especially for larger flexion angles. The second and third theories are the most accepted until now. They state that the patella develops within tendons in response to the mechanical environment provided by the attaching muscles. The second theory analyzed the mechanical conditions (high hydrostatic stress) that (according to previous Carter theories) lead to the differentiation from tendon to fibrocartilage, and then, to bone. The last theory was evaluated using the self-optimizing capability of biological tissue. It was considered that the development of the patella, due to tissue topological optimization of the developing quadriceps tendon, is a feasible explanation of the patella appearance. For both theories, a patella onset was obtained as a structure embedded within the tendon. This model provided information about the relationship between the flexion angle and the patella size and shape. In conclusion, the computational models used to evaluate and analyze the selected theories allow determining that the patella onset may be the result of a combination of biochemical and mechanical factors that surround the patellar tendon development.

Special Considerations for Pediatric Patellar Instability.

Patellar instability in children and adolescents is a challenging subset to treat. Varied forms of instability, ranging from episodic dislocation to fixed dislocation, have been recognized. It is of utmost importance for the treating physician to recognize these different patterns of instability and their associated risk factors, as more complex patterns of instability would require more extensive surgical procedures. Medial patellofemoral ligament (MPFL) reconstruction, by itself, may not suffice or may not be appropriate for the more complex instability patterns. Appropriate and early treatment of such instability in children would allow for functional progression and possible remodeling of the trochlea. However, early treatment has the associated risk of growth disturbances when surgical procedures are performed around open physis or if adult-type bony procedures are performed in children. Recent knowledge about the relationship between trochlea, MPFL femoral attachment, and distal femoral physis could help to advance safe surgical care for these patients. This article reviews the pathophysiology, risk factors, and the existing classification systems for patellar instability in children and adolescents. It focuses on varied surgical techniques, which are unique to the pediatric population, and summarizes the outcomes of these surgical techniques.

On the development of the patella.

The current view of skeletal patterning fails to explain the formation of sesamoid bones. These small bones, which facilitate musculoskeletal function, are exceptionally embedded within tendons. Although their structural design has long puzzled researchers, only a limited model for sesamoid bone development has emerged. To date, sesamoids are thought to develop inside tendons in response to mechanical signals from the attaching muscles. However, this widely accepted model has lacked substantiation. Here, we show that, contrary to the current view, in the mouse embryo the patella initially develops as a bony process at the anteriodistal surface of the femur. Later, the patella is separated from the femur by a joint formation process that is regulated by mechanical load. Concurrently, the patella becomes superficially embedded within the quadriceps tendon. At the cellular level, we show that, similar to bone eminences, the patella is formed secondarily by a distinct pool of Sox9- and Scx-positive progenitor cells. Finally, we show that TGFß signaling is necessary for the specification of patella progenitors, whereas the BMP4 pathway is required for their differentiation. These findings establish an alternative model for patella development and provide the mechanical and molecular mechanisms that underlie this process. More broadly, our finding that activation of a joint formation program can be used to switch between the formation of bony processes and of new auxiliary bones provides a new perspective on plasticity during skeletal patterning and evolution.

The morphometry of patella and patellar ligament during the fetal period.

This study aims to determine the development and morphology of the patella and patellar tendon and to obtain morphometric data about these structures during the fetal period. One hundred five human fetuses (55 males and 50 females) aged 9-40 weeks were used in this study. Fetuses were divided into four groups between gestational weeks; Group I (9-12 weeks), Group II (13-25 weeks), Group III (26-37 weeks), and Group IV (38-40 weeks). The patella and patellar ligament were exposed via anatomical dissection; the dimensions (length, width, thickness) and the width of the lateral and medial articular surfaces of the patella, and the length and width of the patellar ligament, were measured using a Vernier's caliper. No significant differences were observed between genders or sides for any of the parameters (P > 0.05), and a significant correlation was found between gestational age and all parameters (P < 0.001). All parameters of the patella and patellar ligament were found to be different statistically between trimesters (P < 0.05). This study reveals the development, morphological changes, and the morphometric measurements of the patella and patellar ligament during the fetal period. We hope that the present results can be useful for future studies.

The morphological features of the mediopatellar and lateral folds of the developing knee joint: a fetus cadaveric study.

OBJECTIVES: The aim of the study was to evaluate the morphological features of the mediopatellar and lateral folds in fetal knees in the absence of any exposure to certain stress factors such as exercise or trauma. METHODS: The study was performed in the knee joints of 15 fetuses (6 males, 9 females) obtained as spontaneous abortion material at 20-34 weeks of gestation. The mediopatellar and lateral folds of the fetuses were classified into eight subgroups according to the following morphological features: A- Absence of folds; B- Short vertical band; C- Long vertical band; D- Narrow horizontal band; E- Broad horizontal band; F- Horizontal band accompanied by a vertical band; G- Horizontal band without a vertical band; H- Fenestrated band. RESULTS: The synovial membrane, covering the infrapatellar fat pad and forming the alar folds, extended upwards and formed the medial and lateral horizontal folds that covered the inferior part of the posterior aspect of the patella. These horizontal folds were thicker in the lower parts (close to their insertions) and became thinner towards the free ends. The horizontal band of the mediopatellar fold was observed in all cases, with an accompanying vertical band in 76.7% of the cases. A horizontally located lateral fold was absent in both knees of one fetus. The frequency of a horizontally located lateral fold was 93.3% and a vertical fold was accompanying in only 28.6% of these cases. It is of note that the horizontal band of the mediopatellar fold observed in all specimens has never been defined in previous classifications. In 10% of the knees, the vertically located part of the mediopatellar fold presented as a large band extending upward and being squeezed between the articular surface of the patella and the medial condyle of the femur. The lateral fold was observed as a large band in 10% of the knees. Another observation was that the higher level the vertical band of the mediopatellar and lateral folds began, the wider the horizontal band was, occupying more place in the patellofemoral space. It was remarkable that the frequencies of the vertically located parts of the lateral and mediopatellar folds in fetuses were higher than those reported for the adults in the literature. CONCLUSION: Our findings suggest that the resorption process of the mesenchymal tissue, particularly in the lateral part, continues until adulthood and causes age-dependent alterations in the formation of intra-articular folds. The synovial folds occupy more space between the patella and femur in the early stages of life than seen in adults. This may be a more frequent cause of unexplained knee pain in children than expected.

Síndrome de Silver Russel ¿agenesia o retardo del crecimiento rotuliano?: sobre un caso clínico: Hospital Vargas de Caracas Noviembre de 2007 / Syndrome of Silver Russel impotence or retard of the growth rotuliano?: on a clinical case Hospital Vargas de Caracas november of 2007

El síndrome de Silver Russel, está caracterizado por retardo en el crecimiento intrauterino, bajo peso al nacer, facie triangular y alteraciones tanto músculo-esqueléticas como en piel, asociado a anomalías cromosómicas. Describimos el caso de un paciente, masculino de 10 años de edad, en quien durante su valoración clínica se observó ausencia de rótulas, además de rodilla derecha en flexión. Se hace una revisión del tema y de las posibles causas que expliquen la ausencia de las rotulas.

An anatomical and biometrical study of the femoral trochlear groove in the human fetus.

We performed a biometric analysis of the femoral trochlear groove in the fetus and compared our findings with those observed in adults. We studied 44 formalin-preserved fetuses (13-38 weeks) and used digitized images to obtain measurements (alpha angle of the groove, trochlear slopes thetaL and thetaM). A comparison of means between our series and adults was achieved. For each angle of the distal epiphysis (alpha, thetaL, thetaM) there was no significant difference between our fetal series and adults. This is the first biometric study of fetal trochlea. The morphology of the lower femur appears to be the same in the fetus and the adult.

Arthroscopic study of the knee joint in fetuses.

PURPOSE: The purpose of this study was to macroscopically examine the fetal knee joint via arthroscopy. We have attempted to identify and describe the specific characteristics of the fetal knee joint, how it evolves during the last few weeks of intrauterine development, and any possible variations with regard to the adult knee. TYPE OF STUDY: Observational anatomic case series. METHODS: We used 20 frozen fetuses with a gestational age of 24 to 40 +/- 2 weeks, obtained from spontaneous abortions. Examination was performed with standard arthroscopic surgical equipment, using a 2.7-mm optical lens. Whenever possible, we tried to use standard arthroscopic portals. Images were obtained for comparison with the adult knee. RESULTS: Suprapatellar and infrapatellar septa were an almost consistent finding. The suprapatellar septum always opened laterally and was intact in the developmentally younger specimens. We found 2 mediopatellar septa. The femoral attachment of the anterior cruciate ligament (ACL) differed in appearance from that of the adult in that it was more ribbon-like. The lateral meniscus had a more spread-out appearance than its adult counterpart, especially in the specimens of a younger gestational age. We were surprised at the easy accessibility of the popliteal hiatus and the clear arthroscopic vision we were able to obtain of the involved structures. CONCLUSIONS: To our knowledge, this is the first arthroscopic study to target the fetal knee. The results indicate minimal differences when compared with the adult knee, and for some structures, such as the popliteal hiatus, the anatomy seen was easier to discern than in adult knee arthroscopy.

[Anatomic study of the anterior patellar groove in the fetal period]. / Etude anatomique du creusement de la trochlée fémorale chez le foetus.

PURPOSE OF THE STUDY: We performed a biometric analysis of the femoral trochlea in the fetus and compared our findings with those observed in adults in order to search for correlations with other biometric parameters of the femur. MATERIAL AND METHOD: Twenty-two fetuses (44 knees) conserved in formol and free of known orthopedic disease were studied. Fetal age ranged from 26 to 40 weeks. After anatomic dissection, digitalized images were used to obtain angle measurements with a dedicated software. Measurements made on the distal epiphyseal view were: anteroposterior dimension of the condyles, medial and lateral protrusion of the trochlear borders, difference in condyle height, length of the trochleal borders, alpha angle of the trochlear groove, trochlear slope. Measurements made on the AP femoral view were: femoral anteversion, length of the femoral neck, neck-shaft angle. Spearman's test was used to search for correlations. Results were compared with measurements obtained under the same conditions in a series of 32 adult knees published by Wanner. RESULTS: The trochlear alpha angle was 148 degrees (coefficient of variation 4%). The angle was greater than 150 degrees for 18 trochleae. The lateral border of the trochela was higher than the medial border in 37 of the 44 knees. There was no correlation with age and gender. Femoral anteversion was 27.01 degrees, with a high coefficient of variation (46%), and no correlation with the trochlear alpha angle. Comparison with measurements made on the adult knees revealed no significant difference. DISCUSSION: This is the first report of statistically significant biometric data of the fetal trochlea. The morphology of the lower femur observed during the third trimester of fetal live is the same as observed in adults. Morphological changes in the proximal femur occurring during growth do not appear to modify the morphology of the distal femur. The asymmetrical ingression of the patella into the trochlea, characteristic of modern man, is considered to result from bipedalism. Our study would suggest that the anatomic characteristics of the trochlea could have been integrated into the genoma during the course of evolution. This would be in favor of a genetic origin of trochlear dysplasia.

Congenital dislocation of the patella. Part I: pathologic anatomy.

There has been considerable confusion between true congenital dislocation of the patella and other patellar instabilities. Only very few papers describing the anatomical features of congenital dislocation of the patella are found in the literature. The purpose of this paper was to describe the anatomical anomalies found in two cadaver specimens of a true permanent and irreducible congenital patellar dislocation. The quadriceps femoris is short and displaced laterally and acts as a knee flexor. The patella is small, articulating with the outer aspect of the lateral condyle, with no possibility of medial reduction onto the trochlea. Many other anomalies involving the bones, muscles, and nervous structures were found. Congenital dislocation of the patella must be distinguished from other patellar dislocations in children. The severity of structural anomalies is mainly owing to its prenatal onset. Congenital

Fetal and postnatal development of the patella, patellar tendon and suprapatella in the rabbit; changes in the distribution of the fibrillar collagens.

The development of the patella, its associated tendons, and suprapatella of the rabbit knee joint is described from the 17 d fetus to the mature adult. The patellar tendon (ligament) with the patella on its posterior surface is seen in the 17 d fetus and is fully developed by 1 postnatal wk. It is composed of bundles of types I and V collagens separated by endotenons of types III and V collagens. Anteriorly there is an epitenon of types III and V collagens while synovium and a fat pad cover its posterior surface. In the 25 d fetus, the patella is cartilaginous and is separated from the femoral condyles. The cartilage contains type II collagen, but types I, III and V collagens are found along the articular surface. Ossification starts 1 postnatal wk and at 6 wk only the articular cartilage remains. In addition to type II, types III and V collagens are located around the chondrocyte lacunae. The long anterior junction between the patella and its tendon is fibrocartilaginous at 1 wk, but as ossification proceeds this is replaced by bone. Types I and V collagens are found in this region. The suprapatella on the posterior surface of the quadriceps tendon is first seen 1 wk postnatally as an area of irregularly organised fibres and chondrocyte-like cells. Types I, II, III and V collagens are present from 3 wk onwards. It is compared with the fibrocartilage of other tendons that are under compression. The arrangement of the collagens in the patellar tendon is discussed in relation to its use as a replacement for injured anterior cruciate ligaments. It is suggested that the structural differences between the patellar tendon and anterior cruciate ligament preclude the translocated tendon acquiring mechanical strength similar to that of a normal cruciate ligament. The designation 'patellar ligament' as opposed to 'patellar tendon' is questioned. It is argued that the term patellar tendon reflects its structure more accurately than patellar ligament.

Classification of the suprapatellar septum considering ontogenetic development.

At the end of the 4th fetal month, the suprapatellar septum completely separates the knee joint cavity from the suprapatellar bursa. A perforation of the septum normally occurs at the end of the 5th fetal month. Mechanical factors, such as the pressure and friction of the quadriceps tendon on the condylar surface, are said to determine the form and extent of the perforation. Anatomic studies of adult knee joints revealed four variants in the further development of the suprapatellar septum, namely, a completely preserved septum (complete septum), a perforated septum with the communication between suprapatellar bursa and knee joint cavity differing in localization and number (perforated septum), a residual septum in the form of a fold that is almost always in a medial localization (residual septum), or a completely involuted septum (extinct septum). The clinical term "suprapatellar synovial plica" should not be used as a synonym for the expression "suprapatellar septum." The suprapatellar synovial fold corresponds to the residual septum and thus is only one of the four types of the suprapatellar septum.

[Study of the development of the human knee joint]. / Beitrag zum Studium der Entwicklung des Kniegelenks des Menschen.

By studying a complete series of sections of the human knee joint during the period in which the joint gap develops we have found out that the knee joint contains a high broad septum (the mediastinum genus), in which there are many broad vessels. These vessels feed the cruciate ligament anlages, the meniscus anlages and the cartilagenous models of the adjacent bone anlages. In the human embryo the mediastinum genus splits the knee joint into a lateral and a medial half. Communication between these 2 halves is between the small contact surfaces of the patella and femur anlages.

Suprapatellar plica synovialis: a common arthrographic finding.

The suprapatellar structures are often overlooked during double contrast knee arthrography. A plica synovialis suprapatellaris representing a remnant structure from the embryonic septum between knee joint and suprapatellar bursa was identified in 40 of 53 double contrast knee arthrograms. Symptoms including knee pain and clicking have been described in association with the presence of a plica synovialis. Only one of 40 patients in this series, however, was treated for the diagnosis of plica syndrome. Plica synovialis suprapatellaris is a common, usually incidental finding at knee arthrography and should not be mistaken for an adhesion or other capsular abnormality if the clinical findings of plica syndrome are absent.

[Cartilage channels of the human patella up to birth]. / Die Knorpelkanäle der menschlichen Patella bis zur Geburt.

In the human patella from the 4th month up to the birth were examined contents and surrounding structures of vascular channels. Except the articular area the cartilage of the patella is covered by the perichondrium. From here mesenchym and blood vessels enter, and penetrate into the cartilage by forming channels. Dependent on the stages of development the construction of cartilage around the channels is different in comparison with other territories. The findings will be compared with the results from the channels in the cartilaginous anlage of different bones.