Cartilage/bone development/growth, endochrondal ossification, skeletal disorders, intramembranous ossification, muscle tissue, contraction, role of ATP, muscular dystrophies

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Biomedical Science
BMS 460
D.Rao Veeramachaneni

9 September Cartilage and Bone Development and Growth Cartilage and bone are specialized forms of connective tissue derived from embryonic mesenchyme Both consist of cells embedded in an extracellular matrix Cartilage matrix is highly hydrated, being 70 – 75% water. The rest of the matrix is composed of collagen (15 – 20%), for tensile strength, and proteoglycans (2 – 10%) for resistance. It is avascular and has no nerve or lymphatic supply. Bone is the calcified component of the skeleton. The matrix of bone consists of collagen embedded in a ground substance on which is deposited a complex inorganic mineral, hydroxyapatite. Compared with cartilage, bone has a higher metabolic rate, is richly vascularized, and receives up to 10% of cardiac output. Bone has good regenerative potential for self-repair throughout life, whereas cartilage has a very limited capacity for regeneration in response to traumatic injury or disease. Bone develops with or without a cartilage intermediate Via cartilage model Endochondral ossification Without cartilage intermediate Intramembranous (mesenchymal) ossification The transcription factors Sox9 (chondroblasts), Cbfa1/Runx2 and Osterix (osteoblasts) play critical roles in the development of the skeleton – cartilage and bone Chondroblasts (cartilage) and osteoblasts (bone) derive from pluripotent mesenchymal cells when appropriate transcription factors are expressed Cartilage growth Appositional Interstitional – lower, in hyaline matrix Cartilage Hyaline – type II collagen Elastic (arteries) – type II collagen + elastin Fibro (tensile strength) – type I collagen Bone Development: Endochondral Ossification Cartilage – future bone. Entirely covered by a delicate perichondrium A thin collar of bone has formed around the diaphysis Vascularization of the bone collar and hypertrophy of the diaphyseal chondrocytes – called the primary ossification center Blood vessels enter the newly formed medullary cavity and grow toward the epiphyseal ends of the bone, establishing the two epiphyseal growth plates A secondary center of ossification has formed, and the whole bone has elongated owing to chondrocyte proliferation and hypertrophy in the growth plate. Up to this time, the entire developing bone is covered by a perichondrium (where cartilage remains) or a periosteum (where bone has formed). Further lengthening of the bone, appearance of a second center of secondary ossification, and further development of bone vasculature. The cartilage-covered articular surfaces no longer have a perichondrium. An adult bone – the cortical bone has thickened, the bone has achieved its full length and width, the epiphyseal plate have become ossified (“closed”) – epiphyseal line, and the articular surfaces are free of a perichondrium. Mutations in genes encoding chondrogenic/osteogenic transcription factors are the genetic basis of skeletal disorders Mutations in the Sox9 gene cause the rare and severe dwarfism – Campomelic Dysplasia Sox9-null chondrogenic cells remain in perichondrium and do not differentiate into chondrocytes Cbfa1/Runx2 – deficient mice have a skeleton consisting of cartilage without any indication of osteoblast differentiation represented by bone formation and mineralization. In addition, because osteoblasts regulate the formation of osteoclasts, Cbfa1/Runx2 – deficient mice lack osteoclasts. Patients with cleidocranial dysplasia (hypoplastic clavicles and delayed ossification of sutures of certain skull bones) have a Cbfa1/Runx2 type of gene mutation A total lack of expression of the Cbfa1/Runx2 gene determines that the entire skeleton consists only of cartilage An autosomal dominant skeletal dysplasia characterized by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. Bone Development: Intramembranous Ossification Mesenchymal cells differentiate directly into osteoblasts and form bone without a cartilage intermediate Mesenchymal cells aggregate without a cartilage intermediate. This process is controlled by patterning signals from polypeptides of the Wnt, hedgehog, fibroblast growth factor, and transforming growth factor-β families. Mesenchymal cells differentiate into osteoblasts. A bone blastema is formed. Osteocytes within the core of the blastema are interconnected by cell processes forming a functional syncytium. Osteoblasts line the surface of the bone blastema. Bone matrix (osteoid) is deposited by osteoblasts. Later, Ca , transported by blood vessels, is used in the mineralization process and primary bone tissue is formed. Osteoclasts initiate the modeling of the bone tissue. Organization of a primary ossification center Multiple individual trabeculae enlarge by appositional growth and eventually fuse together as a primary ossification center organized during the first stage of intramembranous ossification. Although primary bone tissue formation begins as an interstitial process, it soon becomes appositional. Osteocytes become trapped within the calcified osteoid. At the surface of the osteoid, osteoblasts continue the appositional deposit of matrix, mainly type I collagen and noncollagenous proteins. Several members of the Bone Morphogenetic Protein (BMP) family regulate embryonic development and skeleton formation Several BMPs are also named ‘cartilage-derived morphogenetic proteins’ (CDMPs), while others are referred to as ‘growth differentiation factors’ (GDFs). Some of these belong to the Transforming growth factor-beta (TGF –β) superfamily of proteins. Mutations in BMPs, their inhibitors, or their receptors are associated with a number of inherited human disorders which affect the skeleton. Fibrodysplasia ossificans progressiva Ectopic ossification is observed as lumps in the muscles of the neck and back. Lumps are first noted in children 1 to 3 years old. Ectopic bone is visualized in radiographs after the initial appearance of ossifying lumps. Bone matures and develops a normal trabecular architecture An activating mutation in the gene encoding a receptor for a BMP leading to the transformation of connective tissue and muscle tissue into a secondary skeleton. Muscle Tissue Histologically, muscle tissue is described as being smooth or striated Striated is further subdivided into skeletal and cardiac muscle Since muscle cells are elongated, all three types are called fibers rather than cells Each individual cell/fiber is invested with a delicate external lamina similar to basal lamina Skeletal muscle comprises the major muscle mass of the body and its contraction is under voluntary control. Description: Long, striated cells with multiple nuclei Common locations: In skeletal muscles Function: Contraction for voluntary movements Smooth muscle is widely distributed in many organs, where it may have contractile or supporting functions, or both. Smooth muscle is also found in the walls of all blood vessels larger than capillaries. It is generally referred to as involuntary muscle, since its contraction is regulated by the autonomic nervous system. Smooth muscle fibers exhibit an intrinsic contractility, so they may contract in the absence of external or nervous stimuli; the peristaltic waves of contraction o
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