Musculoskeletal System - Joint Development

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A personal message from Dr Mark Hill (May 2020)  
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I have decided to take early retirement in September 2020. During the many years online I have received wonderful feedback from many readers, researchers and students interested in human embryology. I especially thank my research collaborators and contributors to the site. The good news is Embryology will remain online and I will continue my association with UNSW Australia. I look forward to updating and including the many exciting new discoveries in Embryology!

Introduction

Developing distal phalangeal joint

In the adult, the region where two skeletal bones meet and articulate is called a "joint", that are classified based upon their: anatomical structure, mobility and shape.

In the embryo, the majority of the vertebrate skeleton is initially formed as a cartilage template, that is later replaced by bone except at the interface between two adjacent bones, leaving in the adult a layer of cartilage in this region. The musculoskeletal system consists of skeletal muscle, bone, and cartilage and is mainly mesoderm in origin with some neural crest contribution.


Joint Links: joint | synovial joint | temporomandibular joint | musculoskeletal | cartilage | Category:Joint
Historic Embryology  
1940 Synovial Joints | 1952 Mandibular Joint


Musculoskeletal Links: Introduction | mesoderm | somitogenesis | limb | cartilage | bone | bone timeline | bone marrow | shoulder | pelvis | axial skeleton | skull | joint | skeletal muscle | muscle timeline | tendon | diaphragm | Lecture - Musculoskeletal | Lecture Movie | musculoskeletal abnormalities | limb abnormalities | developmental hip dysplasia | cartilage histology | bone histology | Skeletal Muscle Histology | Category:Musculoskeletal
Historic Musculoskeletal Embryology  
1853 Bone | 1885 Sphenoid | 1902 - Pubo-femoral Region | Spinal Column and Back | Body Segmentation | Cranium | Body Wall, Ribs, and Sternum | Limbs | 1901 - Limbs | 1902 - Arm Development | 1906 Human Embryo Ossification | 1906 Lower limb Nerves and Muscle | 1907 - Muscular System | Skeleton and Limbs | 1908 Vertebra | 1908 Cervical Vertebra | 1909 Mandible | 1910 - Skeleton and Connective Tissues | Muscular System | Coelom and Diaphragm | 1913 Clavicle | 1920 Clavicle | 1921 - External body form | Connective tissues and skeletal | Muscular | Diaphragm | 1929 Rat Somite | 1932 Pelvis | 1940 Synovial Joints | 1943 Human Embryonic, Fetal and Circumnatal Skeleton | 1947 Joints | 1949 Cartilage and Bone | 1957 Chondrification Hands and Feet | 1968 Knee

Some Recent Findings

  1. Computational model of a synovial joint morphogenesis[1] "Joints enable the relative movement between the connected bones. The shape of the joint is important for the joint movements since they facilitate and smooth the relative displacement of the joint's parts. The process of how the joints obtain their final shape is yet not well understood. Former models have been developed in order to understand the joint morphogenesis leaning only on the mechanical environment; however, the obtained final anatomical shape does not match entirely with a realistic geometry. In this study, a computational model was developed with the aim of explaining how the morphogenesis of joints and shaping of ossification structures are achieved. For this model, both the mechanical and biochemical environments were considered. It was assumed that cartilage growth was controlled by cyclic hydrostatic stress and inhibited by octahedral shear stress. In addition, molecules such as PTHrP and Wnt promote chondrocyte proliferation and therefore cartilage growth. Moreover, the appearance of the primary and secondary ossification centers was also modeled, for which the osteogenic index and PTHrP-Ihh concentrations were taken into account. The obtained results from this model show a coherent final shape of an interphalangeal joint, which suggest that the mechanical and biochemical environments are crucial for the joint morphogenesis process.}
  1. The Roles of Indian Hedgehog Signaling in TMJ Formation[2] "The temporomandibular joint (TMJ) is an intricate structure composed of the mandibular condyle, articular disc, and glenoid fossa in the temporal bone. Apical condylar cartilage is classified as a secondary cartilage, is fibrocartilaginous in nature, and is structurally distinct from growth plate and articular cartilage in long bones. Condylar cartilage is organized in distinct cellular layers that include a superficial layer that produces lubricants, a polymorphic/progenitor layer that contains stem/progenitor cells, and underlying layers of flattened and hypertrophic chondrocytes. Uniquely, progenitor cells reside near the articular surface, proliferate, undergo chondrogenesis, and mature into hypertrophic chondrocytes. During the past decades, there has been a growing interest in the molecular mechanisms by which the TMJ develops and acquires its unique structural and functional features. Indian hedgehog (Ihh), which regulates skeletal development including synovial joint formation, also plays pivotal roles in TMJ development and postnatal maintenance. This review provides a description of the many important recent advances in Hedgehog (Hh) signaling in TMJ biology. These include studies that used conventional approaches and those that analyzed the phenotype of tissue-specific mouse mutants lacking Ihh or associated molecules."
  • Precise spatial restriction of BMP signaling in developing joints is perturbed upon loss of embryo movement[3] "Dynamic mechanical loading of synovial joints is necessary for normal joint development, as evidenced in certain clinical conditions, congenital disorders and animal models where dynamic muscle contractions are reduced or absent. Although the importance of mechanical forces on joint development is unequivocal, little is known about the molecular mechanisms involved. Here, using chick and mouse embryos, we observed that molecular changes in expression of multiple genes analyzed in the absence of mechanical stimulation are consistent across species. Our results suggest that abnormal joint development in immobilized embryos involves inappropriate regulation of Wnt and BMP signaling during definition of the emerging joint territories, i.e. reduced β-catenin activation and concomitant upregulation of pSMAD1/5/8 signaling. Moreover, dynamic mechanical loading of the developing knee joint activates Smurf1 expression; our data suggest that Smurf1 insulates the joint region from pSMAD1/5/8 signaling and is essential for maintenance of joint progenitor cell fate."
  • Development of the human shoulder joint during the embryonic and early fetal stages[4] "In our study, serial sections of 32 human embryos (Carnegie stages 16-23) and 26 fetuses (9-13 weeks) were analyzed. The chondrogenic anlagen of the humerus and the medial border of the scapula can be observed from as early as Carnegie stage 17, whereas that of the rest of the scapula appears at stage 18. The osteogenic process begins in week 10 for the humeral head and week 11 for the scapula. At stage 19 the interzone becomes apparent, which will form the glenohumeral joint. In the next stage the glenohumeral joint will begin delaminating and exhibiting a looser central band. Denser lateral bands will join the humeral head (caput humeri) and the margins of the articular surface of the scapula, thus forming the glenoid labrum, which can be fully appreciated by stage 22. In 24-mm embryos (stage 21) we can observe, for the first time, the long head of the biceps tendon (which is already inserted in the glenoid labrum by week 9), and the intertubercular sulcus, whose depth is apparent since week 12. Regarding ligamentous structures, the coracohumeral ligament is observed at the end of Carnegie stage 23, whereas the primitive glenohumeral ligament already appeared in week 10." shoulder | limb
More recent papers  
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Search term: Joint Development | Joint Morphogenesis | Synovial Joint Development | Temporomandibular Joint Development | Shoulder Joint Development

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Mechanobiological simulations of prenatal joint morphogenesis[5] "Joint morphogenesis is the process in which prenatal joints acquire their reciprocal and interlocking shapes. Despite the clinical importance of the process, it remains unclear how joints acquire their shapes. In this study, we simulate 3D mechanobiological joint morphogenesis for which the effects of a range of movements (or lack of movement) and different initial joint shapes are explored. We propose that static hydrostatic compression inhibits cartilage growth while dynamic hydrostatic compression promotes cartilage growth." cartilage
  • The development of synovial joints.[6] "The position of future joints is first delimited by areas of higher cell density called interzones initially through an as yet unidentified inductive signal, subsequently specification of these regions is controlled hierarchically by WNT14 and gdf5, respectively. Joint-forming cell fate although specified is not fixed, and joints will fuse if growth factor signaling is perturbed."
  • Transcription factor ERG and joint and articular cartilage formation[7] "ets transcription factor ERG is part of molecular mechanisms leading chondrocytes into a permanent developmental path and become joint forming cells, and may do so by acting downstream of joint master regulator protein GDF-5"

Joint Types

Joint development 02.jpg

Classification

  • Fibrous (synarthrodial) - immoveable joints found in cranial vault and teeth
  • Cartilagenous (synchondroses and sympheses) - partially moveable joints
  • Synovial (diarthrosis) - freely moveable joints are the most common found in the skeleton

Movement

Mouse neck joint articular cartilage. Cartilage Histology
  • Hinge - (elbow and knee) Flexion/Extension
  • Pivot - (neck, atlas and axis bones) Rotation of one bone around another
  • Ball and Socket - (shoulder and hip)
  • Saddle - (thumb)
  • Condyloid - (wrist joints)
  • Gliding - (intercarpal joints) Gliding movements

Synovial Joint

Skeletal joint cavity development (cavitation) occurs along planes of the future articular surfaces of synovial joints. A number of different markers have been shown to be present in the interzone at the time of cavitation (hyaluronan and hyaluronan synthase, but not chondroitin sulphates).

Fibroblast-like cells (and/or adjacent chondrocytes) with uridine-diphospho glucose dehydrogenase (UDPGD) activity contribute to glycosaminoglycan levels (increases in hyaluronan). These cells are located on the intimal surface of the synovial lining and have been suggested as the possible cavitation mechanism, switching from cellular cohesion to dissociation.[8]

Synovial Joint

Temporomandibular Joint

The temporomandibular joint (TMJ) is a unique synovial joint. It forms from two blastemata that grow toward each another. The articulating surfaces of the joint are not covered by hyaline cartilage, but a fibrous tissue consisting of both elastic and collagen fibres. Finally, condylar bone formation is different from that seen in other growth plates.

Joint components:

  1. mandibular condyle
  2. a fibrocartilagenous disc
  3. the glenoid fossa of the temporal bone.

The skeletal muscles attached to the joint include the lateral pterygoid and temporalis muscles.

Postnatal development[9] [10]

Historic

  1. first stage (weeks 7-8) - blastematic stage, onset of condyle, articular disc and capsule organization. During week 8 intramembranous ossification of the temporal squamous bone begins.
  2. second stage (weeks 9-11) - cavitation stage, corresponding to the initial formation of the inferior joint cavity (week 9) and the start condylar chondrogenesis. Week 11 marks the initiation of organization of the superior joint cavity.
  3. third stage (after week 12) - maturation stage.
  • 2009 Development of the mandibular condylar cartilage in human specimens of 10-15 weeks' gestation using human embryos from the Madrid Collection.[15]


Molecular

Sprouty

  • Spry1 and Spry2 expressed in lateral pterygoid and temporalis muscles.
  • inactivation of Spry1 and Spry2 results in overgrowth of these muscles.[16]
  • in turn disrupts normal development of the glenoid fossa.
  • Sprouty family proteins are evolutionarily conserved inhibitors of tyrosine kinase signaling
  • spry protein is an antagonist of fibroblast growth factor (FGF) signaling
  • 3 different human homologs

Shoulder Joint

This timeline data comes from a recent study of 32 human embryos (Carnegie stages 16-23) and 26 fetuses (9-13 weeks.[4]

Shoulder Development Timeline
Carnegie Stage Event
17 chondrogenic progenitor of the humerus and the medial border of the scapula can be observed.
18 chondrogenic progenitor for rest of the scapula appears.
19 glenohumeral joint will begin delaminating and showing a looser central band (interzone). Denser lateral bands will join the humeral head (caput humeri) and the margins of the articular surface of the scapula, thus forming the glenoid labrum (glenoid ligament).
21 long head of the biceps tendon present
22 glenoid labrum (glenoid ligament) present
23 coracohumeral ligament present
Week
Fetal Week 10 osteogenic process begins in the humeral head. Primitive glenohumeral ligament present
Fetal Week 11 osteogenic process begins in the scapula
Links: shoulder | joint | limb | timeline     Data from human histological study.[4]

Knee Joint

In human embryo at week 7 the femur and tibia cartilage template is present (stage 18), by week 8 the posterior cruciate ligament appears (stage 21), and by stage 23 the knee cavity and the anterior cruciate ligament are both also present.[17]

Joint Morphogenesis cartoon.jpg Knee Morphogenesis
  • a - The first sign of a presumptive joint is a condensation of Col2+ limb bud progenitors at the presumptive joint site.
  • b - Joint specification is marked by induction of Gdf5 in the interzone and downregulation of Col2a1.
  • c - A joint space is formed by cavitation after progenitors for a variety of secondary joint structures are specified from the Gdf5+ progenitor pool.
  • d - Maturation of the synovial joint of the knee occurs during development and early postnatal life.







Adult Knee

  • e - Schematic representation of a healthy human knee.
  • f - Joint health in adult life is affected by genetics and environmental factors such as nutrition and exercise. Loss of joint homeostasis can trigger degenerative joint diseases such as osteoarthritis, which is characterized by degradation of articular and meniscal cartilage, formation of bone spurs and pain.

Figure from recent BMP review.[18]

Joint Abnormalities

FGFR-Related Craniosynostosis Syndromes

Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome

Links: GeneReviews - FGFR-Related Craniosynostosis Syndromes)


Links: skull

Multiple Epiphyseal Dysplasia

Links: GeneReviews - Multiple Epiphyseal Dysplasia)

Arthrogryposis

Arthrogryposis (arthrogryposis multiplex congenital, AMC) is a congenital joint contracture occurring in two or more body regions.

Large range of causes including:

  • single-gene disorders autosomal recessive, autosomal dominant or X-linked traits.
  • part of chromosomal disorders (Trisomy 18, many microdeletions and micro duplications)
  • connective tissue disorders

Temporomandibular Disorders

Links: temporomandibular joint

Osteoarthritis

Clutton's joints

Historic clinical term for a symmetrical joint swelling occurring in patients of both sexes between 5 to 20 years of age with congenital syphilis. Joint swelling is usually in the knees, but can also affect the ankles, elbows, wrists and fingers. Named after Henry Hugh Clutton who first described the condition in 1886.


Links: syphilis)


References

  1. Carrera-Pinzón AF, Márquez-Flórez K, Kraft RH, Ramtani S & Garzón-Alvarado DA. (2019). Computational model of a synovial joint morphogenesis. Biomech Model Mechanobiol , , . PMID: 31863216 DOI.
  2. Bechtold TE, Kurio N, Nah HD, Saunders C, Billings PC & Koyama E. (2019). The Roles of Indian Hedgehog Signaling in TMJ Formation. Int J Mol Sci , 20, . PMID: 31847127 DOI.
  3. Singh PNP, Shea CA, Sonker SK, Rolfe RA, Ray A, Kumar S, Gupta P, Murphy P & Bandyopadhyay A. (2018). Precise spatial restriction of BMP signaling in developing joints is perturbed upon loss of embryo movement. Development , 145, . PMID: 29467244 DOI.
  4. 4.0 4.1 4.2 Hita-Contreras F, Sánchez-Montesinos I, Martínez-Amat A, Cruz-Díaz D, Barranco RJ & Roda O. (2018). Development of the human shoulder joint during the embryonic and early fetal stages: anatomical considerations for clinical practice. J. Anat. , 232, 422-430. PMID: 29193070 DOI.
  5. Giorgi M, Carriero A, Shefelbine SJ & Nowlan NC. (2014). Mechanobiological simulations of prenatal joint morphogenesis. J Biomech , 47, 989-95. PMID: 24529755 DOI.
  6. Khan IM, Redman SN, Williams R, Dowthwaite GP, Oldfield SF & Archer CW. (2007). The development of synovial joints. Curr. Top. Dev. Biol. , 79, 1-36. PMID: 17498545 DOI.
  7. Iwamoto M, Tamamura Y, Koyama E, Komori T, Takeshita N, Williams JA, Nakamura T, Enomoto-Iwamoto M & Pacifici M. (2007). Transcription factor ERG and joint and articular cartilage formation during mouse limb and spine skeletogenesis. Dev. Biol. , 305, 40-51. PMID: 17336282 DOI.
  8. Edwards JC, Wilkinson LS, Jones HM, Soothill P, Henderson KJ, Worrall JG & Pitsillides AA. (1994). The formation of human synovial joint cavities: a possible role for hyaluronan and CD44 in altered interzone cohesion. J. Anat. , 185 ( Pt 2), 355-67. PMID: 7525525
  9. Wright DM & Moffett BC. (1974). The postnatal development of the human temporomandibular joint. Am. J. Anat. , 141, 235-49. PMID: 4416417 DOI.
  10. Mathew AL, Sholapurkar AA & Pai KM. (2011). Condylar Changes and Its Association with Age, TMD, and Dentition Status: A Cross-Sectional Study. Int J Dent , 2011, 413639. PMID: 22114595 DOI.
  11. Moffatt BC. The prenatal development of the human temporomandibular joint. (1957) Carnegie Instn. Wash. Publ. 611, Contrib. Embryol., 36: .
  12. BAUME LJ. (1962). Embryogenesis of the human temporomandibular joint. Science , 138, 904-5. PMID: 13966992
  13. Keith DA. (1982). Development of the human temporomandibular joint. Br J Oral Surg , 20, 217-24. PMID: 6958320 DOI.
  14. Mérida-Velasco JR, Rodríguez-Vázquez JF, Mérida-Velasco JA, Sánchez-Montesinos I, Espín-Ferra J & Jiménez-Collado J. (1999). Development of the human temporomandibular joint. Anat. Rec. , 255, 20-33. PMID: 10321990
  15. Mérida Velasco JR, Rodríguez Vázquez JF, De la Cuadra Blanco C, Campos López R, Sánchez M & Mérida Velasco JA. (2009). Development of the mandibular condylar cartilage in human specimens of 10-15 weeks' gestation. J. Anat. , 214, 56-64. PMID: 19166473 DOI.
  16. Purcell P, Jheon A, Vivero MP, Rahimi H, Joo A & Klein OD. (2012). Spry1 and spry2 are essential for development of the temporomandibular joint. J. Dent. Res. , 91, 387-93. PMID: 22328578 DOI.
  17. Mérida-Velasco JA, Sánchez-Montesinos I, Espín-Ferra J, Mérida-Velasco JR, Rodríguez-Vázquez JF & Jiménez-Collado J. (1997). Development of the human knee joint ligaments. Anat. Rec. , 248, 259-68. PMID: 9185992
  18. Salazar VS, Gamer LW & Rosen V. (2016). BMP signalling in skeletal development, disease and repair. Nat Rev Endocrinol , 12, 203-21. PMID: 26893264 DOI.

Online Textbooks

Developmental Biology Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc. ; c2000 Forming the joints

Reviews

Bender ME, Lipin RB & Goudy SL. (2018). Development of the Pediatric Temporomandibular Joint. Oral Maxillofac Surg Clin North Am , 30, 1-9. PMID: 29153232 DOI.


Articles

Purcell P, Jheon A, Vivero MP, Rahimi H, Joo A & Klein OD. (2012). Spry1 and spry2 are essential for development of the temporomandibular joint. J. Dent. Res. , 91, 387-93. PMID: 22328578 DOI.

Rountree RB, Schoor M, Chen H, Marks ME, Harley V, Mishina Y & Kingsley DM. (2004). BMP receptor signaling is required for postnatal maintenance of articular cartilage. PLoS Biol. , 2, e355. PMID: 15492776 DOI.

Mérida-Velasco JA, Sánchez-Montesinos I, Espín-Ferra J, Mérida-Velasco JR, Rodríguez-Vázquez JF & Jiménez-Collado J. (2000). Development of the human elbow joint. Anat. Rec. , 258, 166-75. PMID: 10645964

Koyama E, Leatherman JL, Shimazu A, Nah HD & Pacifici M. (1995). Syndecan-3, tenascin-C, and the development of cartilaginous skeletal elements and joints in chick limbs. Dev. Dyn. , 203, 152-62. PMID: 7544653 DOI.

Edwards JC, Wilkinson LS, Jones HM, Soothill P, Henderson KJ, Worrall JG & Pitsillides AA. (1994). The formation of human synovial joint cavities: a possible role for hyaluronan and CD44 in altered interzone cohesion. J. Anat. , 185 ( Pt 2), 355-67. PMID: 7525525

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