5 Steps Of Endochondral Ossification

Endochondral Ossification

Endochondral ossification is the procedure by which bone tissue is formed in early fetal development.

From: Comprehensive Biomaterials , 2011

Pathogenesis of Osteochondrosis

Janet Douglas , in Diagnosis and Management of Lameness in the Equus caballus (2nd Edition), 2011

Endochondral Ossification

Endochondral ossification is the procedure past which growing cartilage is systematically replaced past os to form the growing skeleton. ⁷ This process occurs at 3 chief sites: the physis, the epiphysis, and the cuboidal basic of the carpus and tarsus. Chondrocytes in the physis tin can exist divided into a series of layers or zones (Figure 54-3). The zone farthest from the metaphysis is the resting or reserve zone. Adjacent to this is the proliferative zone, in which chondrocytes divide. These cells progress to the hypertrophic zone, in which they enlarge and form ordered columns. During this stage the chondrocytes go surrounded by extracellular matrix that gradually becomes mineralized in the zone of provisional calcification. The chondrocyte columns are and so invaded by metaphyseal blood vessels, and bone forms on the residual columns of calcified cartilage. This mixture of calcified cartilage and immature os (main spongiosa) is then gradually remodeled to produce the mature bone of the metaphysis.⁷ Endochondral ossification, which continues throughout the menses of growth, also occurs in the AECC at the ends of long bones (Figure 54-four).⁸ The chondrocytes of the AECC that are closest to the articular surface produce articular cartilage, whereas those cells closer to the epiphysis participate in endochondral ossification in the same manner as occurs in the physis. It is generally accepted that the growth cartilages of both the physis and the AECC are susceptible to OC.^{ane,three,eight-11}

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9781416060697000547

Diseases of the Bones, Joints, and Connective Tissues

Michelle C. Coleman , ... Scott A. Katzman , in Large Animal Internal Medicine (Sixth Edition), 2020

▪ Pathophysiology

Endochondral ossification is the procedure of bone formation in which cartilage scaffolds, arranged in zones, are gradually replaced past os. It occurs at the articular/epiphyseal and metaphyseal growth plates and at secondary centers of ossification, such as the carpal and tarsal bones. Straight below the articular cartilage is a zone of resting chondrocytes that divide to form the next zone of proliferating chondrocytes. These proliferative cells divide rapidly, organizing into columns perpendicular to the long centrality of growth. The cells not bad in the hypertrophic zone, where the columns become more than organized. The chondrocytes in this zone are surrounded past increasing amounts of extracellular matrix, which becomes mineralized in the zone of calcification. These columns of chondrocytes are vascularized past metaphyseal blood vessels supplying nutrients. It is on these calcified cartilage columns that bone forms, creating the primary spongiosa, which is subsequently remodeled into mature bone.

The exact pathogenesis of osteochondrosis is unclear. The traditional theory is that the process of endochondral ossification is disrupted, resulting in areas of thickened cartilage. The deeper layers of affected cartilage do not receive adequate nutrients, resulting in necrosis of the cells and failure of proper ossification. These retained cartilage "plugs" have less structural integrity than normal cartilage and are prone to damage. Specifically, shear forces interim on the abnormal cartilage can lead to fissure formation, which progress into fragments of cartilage and subchondral os. When compressive forces predominate on an surface area of thickened cartilage, information technology is surmised that infolding of the cartilage plug occurs with normal endochondral ossification proceeding effectually it, perhaps leading to the formation of a subchondral bone cyst.

The traditional theory of defective endochondral ossification may be a simplistic view of a more complex, multifactorial condition. Limited reparative responses of bone and cartilage make information technology difficult to determine whether the origin of a lesion is developmental or traumatic. Ane study failed to distinguish articular cartilage differences in naturally occurring osteochondrosis versus healing osteochondral fragments. ¹³

Computed tomography and magnetic resonance performed on fetuses and foals demonstrated that there was greater cartilage thickness in areas of joints that commonly develop OCD. More specifically, at eight to nine months of gestation, the lateral trochlear ridge of the femur, medial malleolus of the tibia, and distal intermediate ridge of the tibia, all OCD-susceptible sites, had the greatest percentage of cartilage compared to unsusceptible sites. Postpartum, the percent of cartilage in the medial malleolus and distal intermediate ridge of the tibia remained high. These findings suggest that greater cartilage thickness at specific articulation sites could play a function in the development of OCD. ^xiv

Arthroscopic observations of normal-thickness cartilage defects and normal subchondral os, also equally lesions occurring preferentially at unmarried sites at the limits of articulation, suggest causative factors other than defective endochondral ossification. ^xv The development and then spontaneous regression of osteochondrosis lesions in young animals suggest that the condition is a dynamic procedure that tin can be affected by numerous intrinsic and extrinsic factors, and a "window of susceptibility" may exist whereby lesions are constantly irresolute and outcome in the development of normal articular cartilage. Alternatively, these developmental lesions may not regress, leading to osteochondrosis. ¹⁶ It is currently impossible to predict how a lesion may behave while developing; thus handling recommendations should be reserved until the lesion has been fully developed.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780323554459000380

Biologically Inspired and Biomolecular Materials

L. McNamara , in Comprehensive Biomaterials, 2011

2.210.three Os Formation

During embryonic development, os germination occurs by two distinct mechanisms; either endochondral ossification or intramembranous ossification. Bone germination besides persists throughout life to change the geometry of bones and provide larger basic that are sufficient to withstand changes in mechanical loading (modeling), or to supplant aged or damaged bone (remodeling) or make full fracture gaps ( Department ii.210.6 ). Bone formation is typically a 2-pace process whereby an organic matrix (osteoid/cartilage template) is initially laid down by osteoblasts, and then mineral crystals are precipitated and abound slowly over time to produce the composite material.

2.210.3.i Endochondral Ossification

Endochondral ossification is the process past which os tissue is formed in early on fetal evolution. It begins when MSCs start to produce a cartilage template of long basic, such as the femur and the tibia, upon which os morphogenesis occurs. ⁶⁷ The process initiates when MSC cells differentiate to get chondroblast cells ( Figure v(a) ) and form a membrane effectually the template known as the perichondrium. This template grows in length (interstitial growth) and thickness (appositional growth) when the chondroblasts proliferate or more than chondroblasts are recruited from the perichondrium ( Effigy v(b) ). Together, these cells secrete an ECM comprised mainly of collagen and proteoglycans. Over fourth dimension, these chondroblasts differentiate to become chondrocytes and begin to secrete alkaline metal phosphatase, which is an enzyme that acts as a nucleator for deposition of minerals on the template. They also secrete growth factors to promote the invasion of blood vessels into the perichondrium, which is known equally vascularization. This process forms the outer membrane of the os, which is primarily a dense irregular connective tissue known as the periosteum ( Figure 5(c) ). The periosteum is an important source for undifferentiated osteoprogenitor cells. ⁶⁸ It is divided into an outer fibrous layer, which is a source for fibroblasts, and an inner osteogenic layer, which is a source for osteoprogenitor cells that develop into osteoblasts. The periosteum besides provides sites for attachment for ligaments, tendons, and muscles. This process begins in the eye of the template, which is known as the primary center of ossification ( Figure 5(c) ). During mineralization, the chondrocytes undergo apoptosis and the cavities that remain are invaded past claret vessels from the perichondrium. These blood vessels are a source for hemopoietic cells that form the bone marrow and osteoprogenitor cells, which differentiate to go osteoblast cells and secrete bone proteins and minerals. Endothelial cells (ECs) on the lining of blood vessels produce essential growth factors that control the recruitment, proliferation, and differentiation of osteoblasts. ⁶⁹ Therefore, vascularization is an essential requirement for bone formation. ^68,70 A number of other factors regulate the germination of claret vessels, including oxygen tension, mechanical loading, nutrients, and growth factors. ⁷¹ Osteoclasts are also recruited during this time to remodel the template and course a crenel for bone marrow (medullary cavity), and together, these events provide the start bone tissue during fetal development. At nascence, a secondary ossification center appears in the epiphyses of long bones, which is vascularized and forms a cartilage layer known every bit the growth plate ( Figure 5(d) ).

The formation and growth of bones is ongoing throughout childhood and is regulated by the epiphyseal or growth plate ( Effigy 5(d) ), which continues to produce new cartilage, which is replaced by bone, and thereby facilitates lengthening of bones. In adults, lengthening of basic stops and the growth plate fuses and is replaced by bone, known as the epiphyseal line. Basic can go on to abound in diameter effectually the diaphysis by deposition of os past osteoblasts beneath the periosteum, and simultaneously osteoclasts on the interior surface (endosteum) resorb bone to maintain a lightweight structure. The coordinated process of endochondral ossification is essential to the evolution and growth of long basic of the body, but also regulates fracture repair, every bit is discussed in Section 2.210.6.3 .

2.210.3.ii Intramembranous Ossification

During embryonic development, bone formation too occurs by means of a process known as intramembranous ossification, which regulates the formation of nonlong bones such as the bones of the skull and clavicle. The chief divergence between intramembranous and endochondral ossification is that the intramembranous process does not rely on the formation of a cartilage template. Instead, embryonic stalk cells (MSCs) inside mesenchymal tissue of the embryo, derived from chief tissue (germ layers), begin to proliferate and condense to form an amass of MSC cells. This nodule is surrounded by a membrane, and MSCs within the membrane begin to differentiate to first become osteoprogenitor cells so osteoblasts. These osteoblasts line the nodule and secrete an ECM consisting of type I collagen fibrils inside the center of the nodule. Some osteoblasts become embedded within the newly formed matrix, and in this environment, they differentiate and form interconnecting cytoplasmic processes to go osteocytes. The cells on the outer surface grade a periosteum, and os growth continues at the surface of the trabeculae. At this time, the nodule is mineralized to class rudimentary bone tissue that is populated by osteocytes and lined by agile osteoblasts. ⁴⁸ This tissue is known as a bone spicule and many spicules fuse to class trabeculae, known as primary spongiosa, which then fuse to class woven bone. Over time, this woven bone is remodeled to become lamellar os, with concentric lamellae surrounding Haversian systems in what is known equally an osteon. ^48,72,73

Read full chapter

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B9780080552941000684

Mesenchymal Stem Cells as Regulators of the Bone Marrow and Bone Components

50.M. Martinez , ... Northward.A. Chasseing , in Mesenchymal Stromal Cells as Tumor Stromal Modulators, 2017

Osteoclasts in the Formation of the Hematopoietic Niche in the Bone Marrow/Bone

Endochondral ossification is required for the formation of the HSC niche, and it is a process that occurs earlier the appearance of HSCs in the os marrow. HSCs and their progenitors, located in a region of active bone remodeling called endosteum, express receptors that are calcium sensitive and are involved in the retention of these cells near the endosteum, where osteoclasts and osteoblasts promote an increase in calcium levels. ¹⁰⁶

Osteogenesis, osteoclastogenesis, and bone resorption processes are extremely regulated, involving complex cell interactions. Pharmacological treatments such as G-CSF or stress conditions induce HSC mobilization, with osteoclast involvement. ¹⁰⁷ Stress-induced osteoclasts produce proteolytic enzymes such as metalloproteinases, which carve factors involved in the regulation of the HSC niche, thus inducing cell mobilization. ^108,109 Bone mineralization matrix growth factors such as IGF, basic FGF (bFGF), TGFβ, BMP, and PDGF are released during bone resorption and stimulate os formation, ¹¹⁰ while active osteoclasts produce acid and proteases that activate growth factors such every bit TGFβ1, which in turn induce both the migration of MSCs to the resorptive places and their osteoblastic differentiation. ¹¹¹ Osteoblasts and pericytes provide a vascular and endothelial niche where HSCs and progenitors are in close contact with their regulatory chemokines, cytokines, and growth factors. ^{20,25,31,36,39,106} For instance, both the membrane and soluble forms of CXCL12/SDF-1, which is produced past osteoblasts, are the major chemoattractant for hematopoietic progenitors and HSCs. ¹¹² Osteoblasts and MSCs express osteopontin, which is a negative and positive regulator of HSCs, promoting, respectively, their proliferation and apoptosis. ¹⁰⁶ These interactions point to a complex scenario of os germination and resorption crosstalk, with the os-remodeling processes osteogenesis, osteoclastogenesis, and bone resorption probably being involved in regulating the formation of the endosteal HSC niche.

Read full chapter

URL:

https://www.sciencedirect.com/scientific discipline/commodity/pii/B978012803102500015X

Book I

Christa Maes , Henry Chiliad. Kronenberg , in Endocrinology: Adult and Pediatric (7th Edition), 2016

Endochondral Ossification

Endochondral ossification is the mechanism responsible for the formation of all long bones of the axial skeleton (vertebrae and ribs) and the appendicular skeleton (limbs). Nearly of the axial skeleton is derived from cells of the paraxial mesoderm that condense early in embryogenesis on both sides of the neural tube and the notochord. Some cells of this mesoderm form segmented structures called somites, portions of which afterward get the sclerotomes that will give rise to the vertebral bodies. The appendicular skeleton arises from the lateral plate mesoderm. The mechanisms underlying the early on condensation, segmentation, differentiation, and patterning events define the precise system of the individual anatomic elements and their patterning along the proximal-distal, dorsal-ventral, and posterior-inductive body axes. These mechanisms involve actions and cross-talk of several morphogens, including fibroblast growth factors (FGFs), sonic hedgehog (Shh), bone morphogenetic proteins (BMPs), and Wnts, too as control by Notch signaling and by transcription factors encoded by HOX, PAX1, and TBX genes. ^nine

As in intramembranous ossification, the evolution of the long basic proper starts with mesenchymal progenitor cells forming condensations at the sites where the bones volition form. ^ten All the same, in the mesenchymal condensations of endochondral basic, cells practice not differentiate into osteoblasts but instead differentiate into chondrocytes that synthesize a characteristic extracellular matrix (ECM) rich in blazon two collagen and specific proteoglycans. Equally such, a cartilaginous model or anlage is established that prefigures the future os. In mice, these differentiated cartilage structures appear around embryonic day 12, with the limb elements emerging in sequence forth the proximodistal centrality (i.e., hip to toes, shoulder to fingers). The sequential steps of the endochondral ossification process starting from this stage are illustrated in Figure 60-i. Initially, the cartilage further enlarges through chondrocyte proliferation and matrix production. Chondrocytes in the midportion of the bone model and so stop proliferating, undergo further maturation, and ultimately get hypertrophic. These large hypertrophic chondrocytes secrete a distinct matrix, containing type Ten collagen, and then rapidly direct the calcification of the matrix. Concomitantly, the hypertrophic chondrocytes direct the cells surrounding the cartilage element chosen the perichondrium to differentiate into osteoblasts that eolith mineralized os matrix—the "os collar"—around the cartilage template. This bone collar forms the initiation site of the cortical os, the dumbo outer envelope of compact, lamellar bone that provides the long os with most of its strength and rigidity (run across Fig. 60-1).

At this time in development, the cartilage model starts to become replaced past bone, vascular, and marrow elements: the master ossification center (see Fig. sixty-1). The transformation is initiated past the invasion of the hypertrophic cartilage cadre by blood vessels (around embryonic day 14 to 15 in mice). This process is accompanied by apoptosis of terminally differentiated hypertrophic chondrocytes, resorption of the calcified cartilage matrix by invading osteoclasts or related "chondroclasts," and deposition of mineralized bone matrix on the remnants of calcified cartilage past perichondrium/periosteum-derived osteoblasts. Recent studies have visualized the entry of osteoblast lineage cells into the primary ossification center at these early stages, showing a close temporal and spatial association betwixt osteoprogenitors and blood vessels co-invading the developing long bones. ¹¹

With the disappearance of the diaphyseal cartilage (encounter Fig. 60-i), the remaining chondrocytes, restricted to the opposing ends of the long bone, provide the engine for subsequent os lengthening. This process is typified by precise temporal and spatial regulation of chondrocyte proliferation and differentiation, with the chondrocytes get-go flattening out and forming longitudinal columns of rapidly proliferating cells, and next, as they reach the ends of the columns closest to the center of the bones, maturing farther to hypertrophic chondrocytes (Fig. 60-2). Finally, at the edge with the metaphysis (encounter Fig. 60-1), the terminally differentiated chondrocytes are thought to mostly disappear through apoptosis, and the calcified hypertrophic cartilage matrix is progressively replaced with cancellous or trabecular bone (forming the primary spongiosa). This procedure of cartilage turnover and replacement past bone requires adequate neovascularization of the chondro-osseous junction by metaphyseal capillaries (see Fig. 60-1 and cellular details in Fig. sixty-2). Thus, similar to the initial formation of the principal ossification centre, endochondral bone formation at the growth cartilage involves rigorous coupling of vascular invasion with maturation and activity of chondrocytes, osteoclasts, and osteoblasts (for review, see reference 12).

At a sure fourth dimension (around postnatal day v in mice), epiphyseal vessels (see Fig. sixty-one), derived from the vascular network that overlays the cartilage tissue, invade the growth cartilage and initiate the formation of the secondary center of ossification. Every bit a result, discrete layers of residual chondrocytes course true growth plates between the epiphyseal and metaphyseal ossification centers, mediating further postnatal longitudinal bone growth. Ultimately, at least in humans, the growth plates completely disappear (close) at the terminate of adolescence in a process that actively requires the action of estrogen in both boys and girls, and growth stops. Remodeling of existing bone, replacing the primary spongiosa with lamellar bone in the secondary spongiosa and renewing the cortical bone, takes place throughout developed life, ensuring optimal mechanical properties of the skeleton and contributing to mineral ion homeostasis. This continual bone turnover is accomplished through the counterbalanced action of osteoclasts and osteoblasts (run into afterwards) and results in a dynamic organization of honeycomb platelike structures or trabeculae in the interior of the bone that are surrounded by claret vessels and bone marrow and housed within the cortical bone.

The mechanisms of embryonic os development described here are largely recapitulated in the adult upon repair of bone defects. In dissimilarity to soft tissues, which repair predominantly through the product of fibrous scar tissue at the site of injury, the skeleton possesses an astounding capacity to regenerate upon impairment. As such, bone defects heal by forming new bone that is indistinguishable from adjacent, uninjured bone tissue. It has been appreciated for a long fourth dimension that fracture repair in the adult bears close resemblance to fetal skeletal tissue evolution, with both intramembranous and/or endochondral os formation processes occurring depending on the blazon of fracture. This close resemblance has been supported by genetic and molecular studies showing that similar cellular interactions and signaling pathways (see later on) are at piece of work in both settings, ^{viii,13-fifteen} although additionally, some molecules that are disposable for development have been constitute to play essential roles in fracture repair. ^16,17

Read full chapter

URL:

https://www.sciencedirect.com/science/commodity/pii/B9780323189071000603

Skin and Musculoskeletal Pathology

Thomas C. Male monarch Md, PhD , in Elsevier's Integrated Pathology, 2007

Metabolic Bone Disease

Metabolic bone disease includes a diverseness of abnormalities in the endocrine part of the bone in calcium homeostasis as well as abnormalities of mineral deposition in newly formed or remodeled os. Since bony remodeling is a constant process throughout life, fifty-fifty minor persistent abnormalities in os mineralization can eventually outcome in marked changes in bone structure or loss of mineralized bone. Abnormalities of mineralization in growing children cause different clinical features with prominent deformity of long bones.

HISTOLOGY

Endochondral Ossification

Endochondral ossification is the normal process that forms all long bones. After a cartilaginous framework of a os is formed, endochondral ossification results in the sequential conversion and resorption of calcified cartilage and its replacement by bone. Osteoblasts migrate to the ossification front and synthesize bone matrix. Endochondral ossification is a well-ordered procedure that has definite polarity with remainder cartilage on one edge and newly formed osteoid on the other. Trailing osteoid is mineralized in an orderly way to form new mineralized bone.

In long bones, ossification begins in the diaphysis during embryonic development, whereas ossification of the epiphysis does not start until after nascency. In neonates, the ossification fronts movement toward each other until merely the growth plates (epiphyseal plates) remain between the metaphysis and epiphysis. Continued endochondral ossification at the growth plates permits a linear increase in bone length until closure of the epiphyses in late adolescence or early adulthood.

Osteoporosis

Osteoporosis is an extremely common disease in United States and tends to exist near severe in postmenopausal women. Progressive os loss after menopause sets the stage for pathologic fractures in multiple bones. Normally, skeletal density increases during childhood and reaches a peak in immature adulthood in all individuals, with men having greater bone density than women. There is a dull, progressive loss of bone mineral afterwards immature adulthood, and this loss can exist accelerated by inactivity (mechanical stimulation is necessary to maintain os mass), nutritional deficiency, and other factors. The extent of peak mineralization and the charge per unit of bone mineral loss are the key determinants of when (and whether) individuals will develop symptomatic osteoporosis during their lifetime (and be at risk for pathologic fractures).

Most patients with osteoporosis appear to take an unequal balance between osteoblastic and osteoclastic activeness. Over time, bony remodeling (in response to changing mechanical stress) accelerates age-dependent loss of bone mineral. Information technology is at present thought that the predominant defect in nigh patients with osteoporosis is decreased new os formation. Osteoporosis affects bones with a large percent of trabecular bone (metabolically active bone that modulates calcium homeostasis) most severely. For this reason, compression fractures of the vertebrae are very common in osteoporosis, and patients may experience decreasing height and nerve root compression as initial symptoms.

At menopause, there is a marked increase in bone mineral loss that is probably related to differences in cytokine secretion in bony tissue. For instance, increased TNF-α production by macrophages favors the differentiation of macrophages to osteoclasts and tin can enhance bone resorption. Estrogen replacement and calcium supplementation may be helpful in some patients but usually are not sufficient to reverse bone loss. Known genetic chance factors for osteoporosis include polymorphisms in the vitamin D receptor.

Hyperparathyroidism

Increased secretion of parathyroid hormone past the parathyroid glands results in increased osteoclastic activity in os with increased resorption and release of costless calcium into the circulation (Fig. 6-16). Hyperparathyroidism is characterized every bit primary if the aberration resides in the parathyroid glands themselves (as a outcome of either hyperplasia or a functional adenoma). Secondary hyperparathyroidism results from abnormalities in gratis calcium and phosphorus levels in plasma that cause compensatory hyperplasia of the parathyroid glands, which then secrete large amounts of parathyroid hormone. This condition is mutual in patients with cease-phase renal disease and contributes to the bony abnormalities in renal osteodystrophy (see beneath). Severe, prolonged hyperparathyroidism tin effect in the formation of and so-called brown tumors, which are solid aggregates of osteoclasts stimulated by parathyroid hormone. Brown tumors are not true neoplasms, and removal of parathyroid hormone results in their regression. Hypercalcemia and bone mineral loss can besides occur as a paraneoplastic syndrome, which may exist mediated by parathyroid hormone-similar peptides or osteoclast activating factor (OAF).

Osteomalacia

Osteomalacia means defective mineralization of newly formed osteoid. Osteomalacia can result from a deficiency of vitamin D (as occurs in rickets) or from resistance to vitamin D (eastward.grand., abnormalities of the vitamin D receptor). In growing children, abnormal bone mineralization results in weakened long basic that tend to bow and curve, resulting in the characteristic skeletal deformities of rickets. Osteomalacia can likewise outcome from aberrant serum concentrations of calcium and phosphorus in patients with end-stage renal disease (and so-called renal osteodystrophy) that prevent normal formation of hydroxyapatite.

Read full affiliate

URL:

https://www.sciencedirect.com/science/commodity/pii/B9780323043281500127

Clinical signs

Mike Davies BVetMed CertVR CertSAO FRCVS , in Clinical Signs in Humans and Animals Associated with Minerals, Trace Elements, and Rare Earth Elements, 2022

Angular deformity of long bones

Impaired endochondral ossification resulting in abnormal formation of long bones (bowed legs) oft due to premature closure of growth plates (e.g., ulnar) with the connected growth of adjacent bone plate (due east.g., radius)—common in dogs.

Element	Species	Comments
Calcium deficiency	Birds, camels, cats, dogs, foxes, goats, horses, nonhuman primates, reptiles, squirrels	Waterfowl: carpal rotation Lemurs: (Tomson and Lotshaw, 1978). Squirrels: limbs, spine, tail
Calcium toxicity	Dogs	Radius curvus
Copper deficiency	Humans, camels, cats, cattle, pigs, poultry (chicks)	Cats: Plain-featured carpi Pigs: Crooked forelimbs Cattle: Rickets Poutry: Deformed metatarsals
Iodine deficiency	Humans, dogs
Manganese deficiency	Birds, dogs, goats, guinea pigs, pigs, rabbits, rats
Molybdenum toxicity	Horses, rabbits, rats	Horses: rickets
Phosphorus deficiency	Birds, dogs, mink
Zinc deficiency	Cattle	Bowing of hindlegs

DD: trauma to growth plate(southward) resulting in premature closure.

Read full affiliate

URL:

https://world wide web.sciencedirect.com/scientific discipline/commodity/pii/B9780323899765000049

Evolution of the Skeleton

Sylvain Provot , ... Henry Kronenberg , in Osteoporosis (Fourth Edition), 2013

Intramembranous Bone Formation

Both endochondral ossification and intramembranous ossification brainstorm with germination of mesenchymal condensations. During endochondral ossification, these condensations class a cartilage matrix; during intramembranous ossification, mesenchymal condensations differentiate directly into osteoblasts without an intervening chondrogenic phase. In the calvaria, mesechymal blastemas prefigure sites of future skull bones, and calvarial sutures develop where two opposing bone fronts appose ( Fig. 6.7). The sutures are the predominant sites of bone growth, which must be carefully coordinated with enlargement of the underlying brain. The most actively proliferating cells are located at the edges of bone fronts, and this is where the differentiation of cells forth the osteoblast lineage occurs. In the mammalian skull, the frontal and parietal bones, every bit well as portions of the temporal and occipital bones, are derived from the NC (see section patterning the skeleton).

Although the molecular mechanisms underlying intramembranous ossification are not well understood, genetic mutations establish in human syndromes have led to the identification of numerous important regulators. Mutations that bear upon intramembranous ossification are generally manifest as either craniosynostosis, resulting from premature fusion of sutures, or every bit enlarged fontanels, when two skull bones neglect to appose correctly.

One of the start gene products in which mutations were identified was Msx2 [250]. Mutations in Msx2 outcome in Boston-type craniosynostosis [249], and lead to enhanced binding of Msx2 to target DNA sequences [101]. Conversely, haploinsufficiency of Msx2 leads to wide open fontanels in humans [251]. In mice, targeted deletion of Msx2 leads to an ossification defect of the frontal bone, with decreased osteoblast proliferation [100]. The mechanisms of action of Msx2 are unknown, simply it may serve to inhibit expression of bone-specific genes such as collagen I [252] and osteocalcin [253] and direct precursors along the osteoblast lineage [103]. How, if at all, these deportment contribute to the craniosynostosis phenotype is uncertain (run into farther discussion of Msx2 in department endochondral bone germination: osteoblasts).

Although Msx2 was the first mutated factor product linked to craniosynostosis, nigh craniosynostosis syndromes are associated with mutations in FGFRs. FGFs signal via four tyrosine kinase receptors, and craniosynostosis syndromes have been linked to mutations in FGFR1, FGFR2, and FGFR3. The bulk of these syndromes are associated with mutations in FGFR1 and FGFR2, and, in fact, mice lacking FGFR3 practice not have any apparent defects in cranial development [254,255]. Mutations in FGFR1 and FGFR2 associated with Crouzon, Pfeiffer, and Jackson-Weiss syndromes more often than not event in gain of part, for example by causing ligand-independent dimerization by stabilizing intermolecular disulfide bones [256–259]. Two specific missense mutations in FGFR2 lead to increased receptor signaling because the mutant receptors are activated by FGF ligands that exercise not normally activate the receptor [260].

Mice genetically manipulated to express the P250R mutant course of FGFR1, the ortholog of which causes Crouzon syndrome in humans, demonstrate premature fusion of cranial sutures accompanied by increased expression of the osteoblastic transcription cistron, Runx2 [261]. Similarly, activating mutations of FGFR2 in mice result in coronal synostosis [262] reminiscent of Apert's syndrome.

The relevant FGF ligands involved in cranial development are existence investigated. Multiple FGFs are expressed during intramembranous ossification, including FGF2, FGF4, FGF9, FGF18, and FGF20 [198]. Ectopic expression of FGF2 in mice leads to macrocephaly [263] and coronal synostosis [264]. In addition, retroviral insertion in the region betwixt FGF3 and FGF4 leads to increased expression of both in cranial sutures and Crouzon-similar craniosynostosis in mice [265]. In contrast, mice scarce in FGF18 have craniofacial defects and delayed ossification [202,203].

Twist one and Twist 2 are basic helix-loop-helix transcription factors that inhibit the actions of Runx2 in osteoblast development. Twist 1 is coexpressed with Runx2 in calvarial basic, while Twist 2 is expressed in the axial skeleton. Every bit in the human craniosynostotic Saethre-Chotzen syndrome, caused by heterozygous inactivating mutations in Twist 1, haploinsufficiency of Twist 1 in mice leads to craniofacial abnormalities [266,267]. Furthermore, haploinsufficiency of Twist ane can rescue the delayed fontanels seen with haploinsufficiency of Runx2, demonstrating a part for Twist 1 in inhibiting Runx2, through the interaction of the twist box of Twist with the runt domain of Runx2 [268].

In addition to FGF signaling, TGFβ signaling has been implicated in intramembranous bone germination in mice. Germline deletion of TGFβ2 results in mild defects in cranial formation and ossification [269], while double knockouts lacking both TGFβ2 and TGFβ3 accept impaired formation of frontal and parietal bones [270]. A similar phenotype is seen in provisional knockout of the receptor Tgfβr2 in Wnt1Cre-expressing cells [271]. In addition, Prx1Cre-mediated deletion of Tgfβr2 also leads to defects in parietal and frontal bones, indicating a cell-autonomous requirement for TGFβRII-mediated signaling in intramembranous os formation [272].

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780124158535000066

Bone

Brian Thousand. Hall , in Basic and Cartilage (Second Edition), 2015

Subperiosteal Ossification and Suppression of the Cartilage Phase

Intramembranous and endochondral ossification are normally regarded as separate and very different modes of ossification, which they are. This is and so, even though much of the ossification in the long bones of many tetrapods occurs subperiosteally and so is essentially intramembranous; the membrane in this instance is the perichondrium, which transforms into a periosteum (Kronenberg, 2007; Dirckx et al., 2013). Despite the stiff stance taken past Patterson (1977), for whom exoskeletons and endoskeletons were admittedly separate, mixed bones consisting of fused dermal and chondral bone exercise exist; for example, in the skeleton of the striped bass, Morone saxatilis; in fusion between tooth-bearing dermal bones and the perichondral and endoskeletal bones of the visceral arches ^A in zebrafish and cichlids; and in fusion of the endochondral bone that replaces Meckel'due south cartilage (endoskeleton) and dermal mandibular bones in hamsters ²⁰ .

We await these patterns of ossification to be conserved phylogenetically – once an endochondral os, e'er an endochondral bone – and, indeed, phylogenetic conservation is what we run into almost all the fourth dimension. At that place are examples, however, where an endochondral bone in an ancestral lineage has been replaced by a membrane bone in a descendant lineage. The simplest mechanisms would be suppression of the cartilaginous model and formation of bone de novo. Of class, in any such example, nosotros accept to be sure we are looking at the same elements in ancestor and descendant, and that 1 os has not been replaced past another from a different position inside the embryo and/or with a different phylogenetic history.

An oft-cited example is the orbitosphenoid of a Due south American limbless 'worm-lizard' (amphisbaenian), Leposternon microcephalum studied by Bellairs and Gans (1983). Although the orbitosphenoid is an endochondral os in all other species studied, in L. microcephalum, it is a membrane bone with an associated cartilage nodule. This nodule is probably not a secondary cartilage for the two following reasons: (1) It does not lie in the periosteum of the membrane bone; and (ii) secondary cartilages have non been reported from reptiles. Irwin and Ferguson (1986) investigated whether reptiles could form secondary cartilage past making incisions in parietal basic of three species of lizards and 2 species of snakes. Bony union typically occurred by 18 days after incision. Secondary cartilage was never seen; see Effigy 5.iv for the phylogenetic distribution of secondary cartilage ²¹ . The cartilaginous nodule in L. microcephalum could be whatsoever of the following:

•: a remnant of the orbital cartilage, which is present just exceedingly small in this species;
•: a remnant of the cartilaginous model that forms the orbitosphenoid in other species; or
•: a neomorph.

A developmental (and phylogenetic?) series is required to resolve this issue.

Read full chapter

URL:

https://world wide web.sciencedirect.com/science/article/pii/B9780124166783000021

Os Biological science and Fracture Healing

Mandi J. Lopez , in Equine Surgery (Fifth Edition), 2019

Indirect Bone Healing

Healing by endochondral ossification involves sequential biological stages with overlapping transition phases. During the acute inflammatory response initiated by injury, a hematoma forms and is populated by cells from bone marrow as well equally peripheral and intramedullary claret. Proinflammatory molecules such equally tumor necrosis factor-α (TNF-α) and interleukin (IL)-one and IL-6 from macrophages and other inflammatory cells peak inside 24 hours of fracture to heighten extracellular matrix synthesis, stimulate angiogenesis, and recruit equally well every bit directly other inflammatory cells and mesenchymal stem (progenitor) cells (MSCs). ⁴⁰ The proteins remain active beyond the acute inflammatory stage that is usually consummate by seven days. Similarly, members of the transforming growth cistron-β (TGF-β) superfamily, which include multiple bone morphogenetic proteins (BMPs), act in combinations to promote the diverse stages of intramembranous and endochondral bone formation. ⁴¹

At the end of the acute inflammatory phase, in that location is a highly cellular, fibrin-rich callus of loosely organized granulation tissue between the bone ends that is a template for the ensuing callus. Endochondral formation occurs in the matrix template and external to the periosteum. The cartilaginous tissue forms a soft callus around 7 to nine days posttrauma. Concurrently, intramembranous ossification commences from solid bone below the periosteum on each fracture terminate. Angiogenesis during this early on phase is regulated largely by angiopoietin-dependent and vascular endothelial growth factor (VEGF)-dependent pathways. ⁴² Vascular morphogenesis is driven by angiopoietins, primarily 1 and 2. The VEGF pathway supports both vasculogenesis (de novo vessel formation) and angiogenesis (generation of new vessels from existing). A transient claret supply to the callus originates from the surrounding soft tissues and is singled-out from periosteal arteries. As healing progresses, the extraosseous blood supply diminishes.

The repair phase is typically associated with soft callus resorption and replacement with hard callus followed past woven bone. Fracture callus MSCs differentiate into chondroblasts that proliferate and secrete cartilage-specific matrix including collagens blazon II and III and proteoglycans. Chondroblasts mature into chondrocytes that become hypertrophic and surrounded by calcified extracellular matrix. Collagen type I replaces collagen types Two and III, and calcium hydroxyapatite crystals cluster around the fibrils to create a hard callus by around 24-hour interval xiv. M-CSF, RANKL, OPG, and TNF-α drive mineralized cartilage resorption and recruit os cells to form woven bone. As vessels invade to unite fragment vasculature, hypertrophic chondrocytes are removed past chondroclasts and woven bone. Bony, bridging callus is formed as woven os replaces calcified cartilage. This is considered the concluding stride in the reparative phase of fracture healing and the point of clinical union.

The remodeling stage involves a second resorptive phase to remodel the hard callus into a os structure with a central medullary cavity, and it is biochemically reliant on IL-i and TNF-α. ⁴⁰ Hard callus is resorbed past osteoclasts while osteoblasts simultaneously deposit lamellar bone. Mineralized collagen fiber sublayers that are variably oriented etch individual lamellar units that, together, form a complex, multilayered structure. Os remodeling results from weight-bearing stresses that crusade concave surfaces to become electronegatively and convex surfaces to go electropositively charged owing to polarity created when pressure is applied to a crystalline environment. Osteoblastic activity is enhanced on electronegative surfaces and osteoclast activity is higher on electropositive surfaces co-ordinate to Wolff'south constabulary. Successful bone remodeling requires an adequate claret supply and gradual increase in mechanical stability. Without both, an atrophic, fibrous nonunion tin can issue. With good vascularity but unstable fixation, a cartilaginous callus may grade but progress to a hypertrophic nonunion or pseudoarthrosis. ⁴³

Read total chapter

URL:

https://www.sciencedirect.com/scientific discipline/commodity/pii/B9780323484206000752