Cartilage and bone

Osteomalacia 1. What is it? What is it characterized by? What is the result of the disease? 2. What is this called in the growing skeleton?

1. A group of disorders characterized by failure to form normal mineralized matrix. Unmineralized organic matrix forms soft bone. 2. In the growing skeleton this is called rickets.

Osteogenesis imperfecta 1. What is it? What is it characterized by?

1. A group of inherited disorders affecting skeletal structures characterized by thin delicate bones, altered stature and up to hundreds of fractures a year (Type I).

Bone growth 1. How does bone growth occur? 2. Where does addition of new bone occur?

1. Bone can only grow by appositional growth since the matrix cannot expand from within. 2. Addition of new bone occurs on surfaces, e.g. on the trabeculae of spongy bone; or on the walls of resorption cavities created by osteoclasts within compact bone.

Intramembranous ossification 1. What is intramembranous ossification? 2. How does this process occur? 3. How is differentiation regulated?

1. Bone formation in dense connective tissue membranes, e.g. in flat bones of the skull or in the shaft of long bones, is called intramembranous bone formation/ossification. 2. Osteoprogenitor cells differentiate from mesenchymal stem cells and begin to mineralize their surrounding matrix to form bone. 3. The process of osteoprogenitor differentiation to osteoblast and osteoblast secretion of inorganic matrix (osteoid) is regulated by a variety of growth factors and hormones such as several Bone Morphogenetic Proteins, IGF-1, Wnt proteins, etc.

Development and remodeling of long bone 1. What contributes to this process? 2. What is the process of long bone development?

1. Both intramembranous and endochondral ossification contribute to the development and remodeling of long bones. 2. Long bones are first formed from cartilage models in the fetus. Epiphyseal cartilages permit joints to function while bones grow and also create a scaffold for deposition of new bone at the epiphysis. Intramembranous bone formation in the shaft lends support during growth.

Cartilage 1. What are the functions of cartilage? 2. What are the different types of cartilage? How do they differ from one another?

1. Cartilage forms a flexible skeletal support which can grow and provide a substrate for bone formation during development. 2. There are three types of cartilage: hyaline, elastic, and fibrocartilage that differ largely in the fiber content of their matrix.

Growth of the epiphyseal plate 1. How does this process occur? 2. What are the zones of the growing plate? 3. How do osteoblasts contribute to this process? 4. What controls this growth? What else is regulated by these factors? 5. What leads to cessation of growth?

1. Chondrocytes in deeper layers of the epiphyseal cartilage can proliferate to produce elongation. As new cells are produced, however, they proceed on a program that leads to their replacement by bone. 2. The steps in this sequence occur in a series of zones defined in the growing epiphyseal plate: zone of reserve cartilage, zone of proliferation, zone of hypertrophy, zone of calcified cartilage, and zone of vascular invasion, bone deposition and resorption. 3. Osteoblasts in the marrow cavity lay down bone on the residual calcified cartilage. 4. Growth of the epiphyseal plate is controlled by genetics, and hormones and growth factors (excess growth hormone leading to IGF-1 and somatomedin excess causes acromegaly). Cartilage hypertophy and death are also regulated by hormones and factors, such as thyroid hormone. 5. Secondary centers of ossification in the epiphysis are a prelude to the cessation of growth when the entire growth plate is replaced by bone.

Bone and cartilage 1. What does the matrix consist of? 2. What are these tissues derived from?

1. Collagen fibers and glycosaminoglycans (GAGS). 2. Both tissues are of mesenchymal origin.

Osteoporosis 1. What is it? 2. What is it related to?

1. Decreased (porous) bone mass. 2. Related to a decrease in estrogen and decreased bone matrix formation, decreased vitamin D and calcium absorption in alcoholic cirrhosis, and decreased vitamin D, hypercalcemia and secondary hyperparathyroidism in renal disease.

Elastic cartilage 1. Where is elastic cartilage found? What is it similar in appearance to? 2. What is a distinguishing characteristic of elastic cartilage? How can this be visualized? 3. What is the importance of elastic fibers?

1. Elastic cartilage (external ear, epiglottis) is similar in appearance to hyaline cartilage with standard H&E staining. 2. It contains dense bundles of elastic fibers which can be visualized with special stains (e.g. Weigert). 3. Elastic fibers contribute to its deformability and resilience.

Bone fracture repair 1. What are the steps in the process of bone fracture repair?

1. Fibrin in the blood clot at the fracture site first produces a scaffold for organization of fibroblasts as in a scar. These generate a cartilaginous callus or union. The soft callus undergoes a transformation, as above, into a vascularized bony callus. Subsequent remodeling can make the fracture site grossly indistinguishable from the original bone if the fracture is properly reduced (apposed).

Fibrocartilage 1. Where is it found? What is an important structural/ compositional characteristic? How can this be identified histologically? 2. What other structure does it resemble? How does it differ from this structure?

1. Fibrocartilage (intervertebral discs, pubic symphysis, tendon insertions on bone) has a dense network of collagen (Collagen Type I) fibers that stain with eosin. 2. It looks very much like dense regular connective tissue with differences in lacunar arrangements and fiber arrays that are sometimes pinnate rather than linear in their organization.

Paget's disease 1. What is it? What is it associated with?

1. Generalized skeletal disorder associated with thickening and weakening of bones related to disregulation of osteoclastic and osteoblastic activity.

Osteocytes 1. What are osteocytes? Where are they found? 2. How do these cells interact with the matrix? How do they communicate? 3. What is their function?

1. Osteocytes are mature bone cells that reside in lacunae surrounded by bone matrix which they have produced. 2. These cells send spiderlike cytoplasmic processes into tiny canaliculi in the matrix. They communicate with other osteocytes via gap junctions between these processes, hence forming a cell network within the bone. 3. They function in turnover and maintenance of their surrounding matrix largely through their ability to sense mechanical stress on bone. An ability to deposit or remove calcium (e.g. in osteocytic osteolysis) from bony matrix makes them key players in calcium homeostasis.

Microanatomy of compact bone 1. What are Haversian systems? What do they contain? 2. What are Volkmann's canals? What is their function? 3. Where are osteoclasts found? What is their role? 4. What are resorption cavities? What are these cavities often cross sections of? 5. How are new osteons produced? What is the difference between primary and secondary lamellae? 6. What is a disease of the bone that can occur from an imbalance in the resorption and formation of bone? What can exacerbate this process?

1. Haversian systems (osteons) are cylindrical units of compact bone with concentric lamellae organized around the axis of the Haversian Canal. The canal contains a neurovascular bundle consisting of an artery, vein, and nerve. 2. Volkmann's canals interconnect Haversian canals and so appear to be perpendicular to the longitudinal axis of osteons. 3. Osteoclasts can be found periodically at the trabecular surface, or in erosion pits called Howship's lacunae. Attachments at their perimeter and ruffled border at the bony surface create an acidic microenvironment for demineralization and lysosomal digestion of the organic matrix. 4. Resorption cavities are sites of bone removal that create larger spaces intersecting the boundaries of osteons. These cavities are often cross sections of tunnels called cutting cones in which osteoclasts spearhead bone removal at the tip of the cone. 5. New osteons are produced by laying bone down within previous sites of erosion so that the lamellae are laid down from the outside in, the newest being those immediately surrounding the Haversian Canal, the oldest at the perimeter. The lamellae of complete osteons are called primary lamellae. If partially eroded, they persist as residual lamellae, or secondary lamellae between fully formed primary osteons. 6.When resorption exceeds new bone formation in osteoporosis the bone become riddled with holes (resorption cavities) and loses its structural integrity. This process is exacerbated by exogenous steroids.

Bone 1. How does the vascular state of bone compare to that of cartilage? 2. What is the matrix composition of bone? What is an important complex found in bone matrix?

1. In contrast to cartilage, bone is highly vascular. 2. Bone has both an organic and inorganic matrix. The organic matrix is collagen rich (Type I) and accounts for the eosinophilia of demineralized preparations. Within this fibrillar matrix, mineralization produces a crystalline inorganic matrix composed of hydroxyapatite, a Ca(PO4) rich complex.

Endochondral ossification 1. What is endochondral ossification? 2. How does this occur?

1. In the development of fetal bones and in the growing epiphyses of long bones bone replaces cartilage - a process called endochondral ossification. 2. The cartilage model provides a flexible structure for growth (interstitial & appositional) and remodeling of the immature skeleton.

Features of cartilage 1. What is the matrix composition of cartilage? 2. Where are chondrocytes found? What can groups of cells indicate? What are these groups of cells called? 3. What is perichondrium? What type of structure can lack a perichondrium? Why is this important? 4. How does cartilage grow? 5. What is the vascular state of cartilage?

1. It contains acidic chondroitin sulfate and keratan sulfate rich GAGs. Collagen (Type II) fibrils restrict distension against an internal pressure created by hydration of GAGs. Additional collagens, such as Type IX add to the structural characteristics of the matrix. 2. Chondrocytes are found in lacunae. Groups of from 2 to 8 cells in one lacuna suggest that a cell has divided but that the daughter cells have not yet produced sufficient matrix to be separated. These are called isogenous groups. 3. Perichondrium is a cellular dense CT layer at the surface which can give rise to new chondrocytes. The articular surface of joint cartilages, however, lacks a perichondrial layer accounting in part for the poor capacity of articular cartilage to repair after injury. 4. Cartilage is capable of two forms of growth. Interstitial growth occurs from within by division of chondrocytes and expansion of the flexible matrix. Appositional growth occurs from the perichondrium where cells on the inner surface give rise to new chondrocytes. 5. Cartilage is avascular. Lacking a capillary network, chondrocytes are nourished by diffusion through the cartilage matrix.

Osteoblasts 1. What are osteoblasts? What is their function? 2. Where are osteoblasts found?

1. Osteoblasts are bone cells active in proliferating and/or producing new organic bone matrix (called osteoid). 2. These cells are typically found on bone surfaces where they lay down new matrix during appositional growth.

Osteoclast and osteoblast regulation 1. How do osteoclasts develop? What is involved in the stimulation of development? 2. How do osteoclasts bind to the bone matrix? 3. How can osteoblasts affect osteoclast activity? 4. How can osteoclast activity be directly regulated?

1. Osteoclast development from monocytes is stimulated by both cytokines (notably M-CSF and RANKL) and direct interaction with osteoblasts. 2. Mature osteoclasts bind to bone matrix proteins via cell membrane integrins. 3. Parathyroid hormone activity through osteoblasts stimulates osteoclast activity. 4. Direct inhibition of osteoclastic activity can occur by calcitonin binding to osteoclasts.

Osteoclasts 1. What are osteoclasts? 2. Where are they found? 3. How can they be distinguished histologically? What may they be confused with? How can they be differentiated from these other structures?

1. Osteoclasts are multinucleated giant cells that attach to bony surface, remove inorganic matrix and digest organic matrix. 2. They are often found in pits (Howship's lacunae) that they have created on the bony trabecular surface of spongy bone; or, they may be active in resorption cavities within in compact bone. 3. They are conspicuous in having at least 3-8 separate nuclei visible in cross sections; not to be confused with megakaryocytes in the marrow cavity which are large polyploid cells that have a single lobulated nucleus rather than multiple nuclei and are not attached to the bony surfaces.

Classification of bone 1. What is spongy bone? What are some structural features? What is its function? What permeates the spaces between bony spicules? 2. What is compact bone? What are some structural features? What is a structure it may lack?

1. Spongy [trabecular, alveolar, cancellous]: an interconnected network of trabeculae or bone spicules provide a supporting framework beneath compact bone which can remodel in response to stress. Marrow permeates the spaces between bony spicules. 2. Compact [lamellar, Haversian, cortical, compacta]: the dense outer shell has subunits consisting calcified layers arranged in concentric layers or lamellae (Osteons, Haversian systems) around a core of vessels and nerves. May lack regular Haversian systems e.g. with woven bone.

Architecture of a long bone 1. What is the head of the bone called? What is a structural feature? 2. How is the head of the bone attached to the shaft? What is the attachment called? What is the shaft called? What can be seen in this intermediate region? 3. What does the marrow cavity contain? 4. What lines the outside of the bone? What are some features of this structure?

1. The epiphysis is the head of the bone, usually with an expanded surface on which the articular cartilage is attached. 2. The epiphysis is connected to the shaft, or diaphysis, of the bone at a region called the metaphysis. In this intermediate region one can see remnants of the growth plate, i.e. the epiphyseal plate. 3. The marrow cavity contains red marrow (hematopoetic) or more fatty yellow marrow which increases with age. 4. A dense periosteum lining the outside of the bone has an inner cellular osteogenic layer which can give rise to new bone on the outside; a single layer of osteogenic cells lining the marrow cavity is called the endosteum.

Microanatomy of spongy bone 1. Where are osteocytes found? 2. What covers the surface? Why is this important? What constitutes the internal structure? What do the internal cells resemble? 3. How are osteocytes nourished?

1. Thin anastamosing trabeculae contain entrapped osteocytes. 2. A layer of osteoblasts cover the surface producing a layer of new organic matrix called osteoid on the surface of the mineralized trabeculae. A similar layer of cells on the inner surface of the marrow cavity forms the endosteum. These osteogenic cells resemble a low cuboidal epithelium, although technically they are not epithelial. 3. Since the trabeculae are thin and surrounded by sinusoidal capillaries of the marrow cavity, osteocytes are nourished by diffusion from the surface through canalicular channels.

Hyaline cartilage 1. What is the importance of hyaline cartilage? 2. What is its role?

1. This type of cartilage forms the bulk of the embryonic skeleton. 2. It retains a supporting role in the adult in some locations (e.g. costal-chondral junctions, external ear, nose, eustacian tube), but largely functions to resist compressive forces and to provide smooth surfaces for articulation at diarthrodial joints.

Osteoarthritis 1. What is its rate of occurrence? 2. What characterizes OA? What is the result of these factors?

1. Very common (85% incidence by age 75). 2. Characterized by chondrocyte death and loss of joint cartilage, inflammation of synovial membranes, narrowing of the joint space, thickened subchondral bone and development of osteophytes. Result is a painful nonfunctioning joint.

Resident cells of cartilage are called (1) and resident cells of bone are called (2).

1. chondrocytes 2. osteocytes