-Support and bears wieght of the body

-Protects vital structures and organs

-Acts as lever for muscle contraction

-Mineral reservior

-2 Epiphyses (heads)

-1 Diaphysis (shaft)

-Metaphyses are cone chaped and join shaft to heads

-Metaphyseal region contains trabeculae/columns of cartilage and bone

-Extends between epiphyses (heads)

-Contains a Central Marrow/Medullary cavity which is surrounded bye mostly Compact Cortical Bone

-Mostly Spongy Bone with shell fo compact bone around it

-Articular suface covered by Hyaline Cartilage

-Cone shaped region connecting Epiphysis to Diaphysis

-Represents transition between the 2 parts

-Dense, Solid and Cortical

-There is NO marrow tissue in cortical bone

-Does have some vascular CT

-Spongy Bone composed of slender irregula trabeculae/bars of calcified matrix

-These branch and form a network

-Contains lots of soft CT that occupies Marrow spaces between trabeculae

-Soft tissue between trabeculae of Cancellous bone

-Within central Medulary Cavity

-Either Red Hemopoietic or Yellow Fatty

-Fibrous CT that covers outer surfac of Cortical bone

-Does NOT cover articular cartilage or where ligaments/tendons insert

-Has outer fibrous and inner cellular layer

-Periosteal collagen fibers that penetrate outer region of bone matrix

-Connects Periosteum to Bone

-Counterpart to periosteum, lines Inner surface of bone

-Surounds the Medullary cavity

-Has both Osteogenic and Hemopoietic potential

-The layers of mineralized matrix in bone

-Layering due to the REGULAR orientation of collagen fibers in each layer

-Collagen fibers in adjacent layers are oriented at a different angle

-Destroys soft tissue elements (bone cells) and decalcified sections

-Retains mineral content but lacunae and canaliculi appear black and empty

-Bone stains Pink when fully mineralized and Blue where calcium salts remain

-Bone sectioned after no/partial decalcification

-Calcifed areas are Blue

-Decalcified are Pink from Type I collagen and some glycosaminoglycans in ground substance

1. Osteoblasts

2. Osteocytes

3. Osteoclasts

Osteoblasts Part 1

-Come from Mesenchymal cells and rim the surface of bone matrix

-Young ones are "Epithelioid" in shape (arranged like Simple Colum. Ep)

-Associated with BONE FORMATION

-Found on surfaces with GROWTH potential

 -Found in cellular layer of Periosteum, Endosteum,and rim around Trabeculae

-Communicate by Gap Junctions with Osteocytes

-Nuclei at end of cell AWAY from bone surface

-Cytoplasm is basophilic from lots of RER

-Resting ones become SPINDLE shaped

-Secrete OSTEOID (bone matrix) : all bone elements except for minerals

Have receptors for:

1. Cytokines

2. PTH

3. 1,25-Vitamin D

4. Estrogen

 (Key regulators of bone turnover)

Do NOT have receptors for Calcitonin

-Major source of the cytokines which are Potent stimulators of bone resoption

-Participate in Osteoclastogenesis at early and late stages

-Actually osteoblasts that have trapped themselves in the Osteoid they secrete

-Occupy Lacunae/small spaces in the organic matrix

-Organic matrix calcifies to become BONE/mineralized matrix

-Osteocytes completely fill the lacunae

-Canaliculi channels radiate away from Lacunae and link them

-They contain oteocyte cytoplasm and canalucular extracellular fluid

-This fluid fills the "Periosteocytic Space"

-This lies between osteocytes and bone matrix

-In young bone, Osteocytic Cytoplasmic processes are long enough to contact adjacent cells

-Use Gap Junctions for passage of homones, ions, etc. in a "bucket brigade" fashion

-Osteoblast in periphery are also linked to osteocytes to form an Osteoblast-Osteocyte Complex

-Allows osteocytes to maintain surrounding bone matrix by transporting materials between blood and matrix

-Some exchange can pccur between osteocytes and blood vessels via the Canalicular Extracellular Fluid

-Increase dissociation of Ca and CaP from bone

-Ca pumps in osteocytes and osteoblasts pull Ca ions from matrix into the CE Fluid, then into plasma

-Ca ions can also go directly into CE fluid then to plasma

-This process is RAPID and Ca is taken from recently formed crystals

-Does NOT Decrease Bone Mass!

-Large, Multinucleated, Derived from Bone Marrow Stem Cells which are also precursor to Monocytes

-Motile with numerous processes

-Found in Howship's Lacunae (resorption cavities)

-Attached to matrix by Integrin Receptors

-Have Several regions within cytoplasm

1. Basal Zone - Side of cell AWAY from resorption cavity

2. Ruffled Border -part of cell ADJACENT to resorbing bone

3. Clear Sealing Zone - surround periphery of ruffled border, contain actin + integrins to help attach cell to bone

4. Vesicular Zone - between basal zone + Ruff. Bord., have vessicle with hydrolytic enzymes

-Regions lying between osteoclast membrane and bone

-One wall is bone surface, others are cell membrane

-Sealed off by Clear Zone

-Ruffled Border projects into it

-Osteoclast controls reaction in the enclosed area

-Cell produces acids and enzymes to break down bone

-Are actively sythesized (Acid Phosphotase, Cathepsin, Collagenase, Gelatinase)

-Secreted through Ruffled Border into SubO compartment

-Transport and targeting of enzymes requires Mannose-6-Phosphate receptors

-Carbonic Anhydrase forms Carbonic Acid from Co2 and H2O

-H dissociates, pumped into compartment, reduces pH

-HydroxyApatite crystals released via digestion of their links to collagen

-Low pH dissolves crystals, enzymes degrade matrix

-Residues are internalized by osteoclast and released into capillaries

Modulated by: PTH, Vitamin D, Cytokines

-Activity of most of these factors is mediated by Osteblasts

-So, Osteoblasts stimulate Osteoclast

-Osteoclasts DIRECTLY inhibited by Calcitonin

IL-1, IL-3, IL-6, IL-11, TNF, GM-CSF and M-CSF

and RANKL

These are all produced by Osteoblasts

[image]

1. IL-1 and TNFa turn Monocytes into Preosteoclasts

2. Osteoblasts release IL-6, M-CSF, GM-CSF, PGE2 and RANKL (which binds to RANK)

3. Preosteoclast turn into Osteoclasts

1. OPA

2. AMG 162

3. Calcitonin

4. Estrogen

5. INF

6. IL-4

7. IL-13

-Monstly Degredation products of Type I collagen:

1. Hydroxyproline

2. Pyridinium cross links

3. Type I Telopeptides (Can be checked in Urine!)

4. TRAcP 5b (osteoclast enxyme)

5. BSP

6. Urinary Ca levels

7. PTH-related protein (produced by tumors that can cause hypercalcemia)

-Bone is a mineralized CT

-Matrix has both Organic and Inorganic components

-Main components is Type I Collagen (90%)

-Orientation of fibers decides if it is Lamellar or Non-Lamellar bone

 -Ground substance is less sulfonated than Cartilage

-Proteoglygans have some sulfonated glycosaminoglycans (Chondroitin + Keratan Sulfate)

The proteoglycans are linked by Hyaluronic Acid to for aggregate glycoproteins:

1. Osteocalcin (unique to bone, good for measuring osteoblast activity)

2. Osteopontin

3. Bone Sialoprotein

Direct/Indirect products of Osteoblast activity:

1. Alkaline Phosphatase ALP ***

2. Osteocalcin

3. Type I Collagen Propeptides (N + C terminal are cleaved before collagen assembly by osteoblasts)

-Narrow seam of premineralized uncalcified matrix covering Surface of mineralized bone

-Adjacent to secretory ends of osteoblasts

- 15-20 day lag between formation of organic matrix and its mineralization

-Calcium Phosphate arranged in Apatite pattern

-"Unit Cell" is lowest amount of ions that can form a relationship: Ca10(PO4)6(OH)2 

-Stack into crystal lattice

-Layer of water called Hydration Shell surrounds each crystal

-Each crystal has 3 surfaces

-Process not fully understood

-Requires Osteoblast and richly vascular CT

-Stuff involved includes:

Ca, P, PTH, Vit D, Enxymes, Collagen, etc.

-Inorganic ions transported into osteoid eith through or between Osteoblasts

Depends on a few factors:

 1. Homogenous Nucleation - local increase in Conc. of ions -> crystal formation

2. Heterogeneous Nucleation - requires a nucleating substance that lowers energy barrier needed for precipitation in absence of local ion concentrations

3. Mineralization inhibitors must be inactivated

-Spherical shaped, membrane bound structures

-Arise from budding off Osteoblasts and enter osteoid

-Seen ONLY IN INITIAL PHASE of mineralization

-They create microenvironment where all conditions needed to initial mineralization exsist

Contain:

-Ca pumps: bring Ca into the vesicle

-Ca-binding lipids: destroy calcification inhibitors

-Alkaline Phosphatase

-1st apatite crystal forms in vesicle, gets bigger and ruptures vessicle

-Starts chain reaction of independent crystal growth

-Mineralization occurs in close relationship to collagen during formation of collagen based calcified tissues

-Crystallites initially form in holes/gap zones of tropocollagen molecules within microfibrils

-Group of enzymes important for mineralization

-Serum concentration used to diagnose Bone Disease

-Sites effected are blood vessels, Osteoblast Cell Membrane and Osteoid

-Provides Phosphate Ions: hydrolyzes them from organic radicals or cleaves pyrophosphate

-Bone Sialoprotein and Phosphoproteins might be nucleators in Hetero. Nucleation

-Vit D might enhance synthesis of Ca binding proteins in Osteoid

-PTH, GH, Calcitonin, Estrogen are important in bone metablism

Classified on basis of:

1. Microscopic appearance: Lamellar or NonLamellar

2. Gross appearance: Compact or Cancellous

3. Method of formation: Membranous or Endochondral

-Matrix appears layered; Collagen fibers in regular orientation

-Fibers parallel within layer, but each layer is different orientation

-Lacunae are ellipsoid, arranged in concentric rings between lamellae, joined by canaliculi

-Lamellar bone formed Slowly!

-No Layers, collagen is a big mess

-More numerous round lacunae randomly scattered in matrix, connected by canaliculi

-Also called Woven/Immature/PRIMARY Bone

-Laid down Rapidly

-1st type of bone formed -> later replaced by Lamellar

Compact: composed of solid blocks of Osseous Tissue

-Occupies Cortical Regions of bones

-Forms cortex of bones and surrounds cancellous

Cancellous: spongy, composed of slender trabeculae/bars of mineralized matrix separated by soft marrow

-Always surrounded by some layer of cortical bone

Found in:

1. Prenatal bones

2. Bony sutures of Skull Flat Bone

3.Tendon attachments to bone

4. Sites of fracture repair

5. Some bone diseases

Compact Lamellar Bone

-Forms cortices of mature bones

-Has a complex structure with Rich vascular supply

-Organized into Osteons, Interstial Lamellae, and Circunferential Lamellae

-Have a central vascular Haversian Canal surrounded by several concentric lamellae

-Oriented parallel to long axis of long bone

-Interstitial Lamellae are partially absorbed Osteons

-Continuous layers on the external and internal surfaces of compact bone

-Outer external: adjacent to Periosteum CT that contains Osteoprogenitor cells

-Internal: adjacent to similar Endosteum CT, oriented oblique to long axis of long bone

-Internal carries blood vessesl from Peri and Endo to connect with Haversian Canals

Trabeculae can be:

-Lamellar in mature bone

-Non Lamellar: usually in primary bone or bone diseases

-Show relationship between compact and cancellous bone

-Compact covers body, ramus, and alveolar process of mandible

-Cancellous bone forms trabeculae network within

-Ultimately forms the Alveolar Bone Proper, Cribiform Plate, and Lamina Dura

-Cortical layer covering alveolar process is thin

-Outer plates of AP are continuous with cortical bone on buccal and lingual aspects

 -Inner Plates surround tooth roots and collegen from Perio. Lig. inserts into them

 -Inner plates known as Alveolar Bone Proper, Cribiform Plate (from small blood vessel openings) and Lamina Dura (hard dense layer)

-Bone arises from Mesenchyme OR by replacing existing cartilage

-Both begin intially with Primary Non-Lamellar bone

-Soon replaced by Mature Lamellar bone

 2 Types of formation:

1. Membrane Formation (from mesenchyme)

2. Endochondral Formation (replaces cartilage)

-From mesenchyme, no former cartilage

Types of bone like this are:

-Flat bonesof the skull

-The Maxilla

-Most of Mandible

-Circumference of long bone shafts

-Mesencyme cells with Foci radpidly proliferate -> produce dense cellular region

-Cells enlarge, develop basophilic cytoplasm from RER

-These Osteoblasts secrete Osteoid matrix

-They form rim around the Osteoid

-Calcification begins in middle of surrounded area

- Spicule enlarges, some osteoblasts get trapped -> Osteocytes

-Osteoblast + Osteocytes keep in contact via processes

-Osseous Spicules continue to enlarge by apositional growth

-Neighboring Foci then develop irregular shaped Spicules

-These enlarge, fuse, and form trabeculae of cancellous bone

-Growing trabeculae are surrounded by vascular mesenchyme

-Red marrow develops between trabeculae

-Periosteum and Endosteum arise on outskirts of areas that do not mineralize

Bone replaces cartilage in:

-Long + short bones of limbs

-Base of skull

-Pelvis

-Vertebrae

Cartilage is resorbed and then replaced!

-EO of long bone occurs wiwthin small cartilage model that has similar shape of future bone

-Model has Epiphyses and a Diaphysis

-Diaphysis is surrounded by Perichondrium

-Perichondriom becomes Periosteum -> deposits layer of membrane bone on model at mid shaft

-Region encircles around mid-portion of shaft and thickens

-Trabeculae of mem. bone widen, cancellous bone becomes compact

-Once reaches certain thinkness -> bone added to surface while internal area is resorbed 

-Mid-region becomes Primary Ossification Center

-Chondroblasts in region enlarge within their lacunae

-Cartilage matrix reduced to narrow ribbons

-Residual cartilage matrix undergoes calcification

-Enlarged chrondroblast are cut off from vascular supply and die

-Surrounding CT from Periosteum invades the P.O.C.

-Creates primitive marrow cavity at center of diaphysis

-Some cells invadingare osteoblastic or hemopoietic

-Osteoid and thin layer of bone deposited around calcified cartilage ribbons

-Then Osteoid, bone, Cal. Cart. is Resorbed by osteoclasts

-This expands the marrow cavity

-This occurs at both ends of POC, resulting in 2 regions of occification

-This whole process of cartilage proliferation, calcification, bone formation and resorbtion is continued towards epiphyses

-The rows of proliferating and calcyfying cartilage are known as Metaphyseal Columns (located within metaphyses)

-This process produses bone with transient existance (forms then rapidly resorbed)

Consequences:

1. Starting at middle forces epiphyses away from eachother ->elongation

2. There is explansion of central marrow cavity

3. Bone surrounding shaft is actually formed from Membrane Bone

-Secondary Ossification Centers appear at center of each epiphysis

-Similar process to before, but extedn radially in all directions

(fingers and toes are mini long bones with one SOC and form this way too)

-Zone of cartilage between Epi. and Meta. is called Epiphyseal Plate

-Proliferates on both surfaces

-Growth on shaft aspect -> metaphyseal columns and MAIN factor to diaphysis elongation

-Cartilage formed on Epip. aspect responsible for radial growth

-Completion of diaphysis elongation coincides with disappearance of Epiphyseal Plates

-Known as Fusion/Epiphyseal Closure

-Once this happens, Bone can no longer increase in length!!!

-Subperiosteal bone encircling diaphysis is formed from membrane bone (mesenchyme)

-Its a layer of Primary Non-lamellar bone

-Widening trabeculae transforms cancellous bone to compact

-This is then resorbed and replaced by compact lamellar via remodeling process

-Cartilge on epiphysis becomes Articular Cartilage

-First formed Primary Bone is NON-lamellar

-Initally cancellous, some area remain spongy

-Eventually, Non-lamellar trabeculae are replaced by Mature Lamellar Cancellous Bone

-Primary cancellous becomes compact where trabecule thicken and destroy adjacent marrow

-If they enlarge sufficiently, Primary Cancellous Bone becomes Compact Non-Lamellar Bone

-Compact Non L bone is resorbed, then replaced by tunnels of vascular tissue that burrow into Primary Bone

-Osteoblast deposit osteoid in tunnels

-Collagen fibers orient in same direction

-Mineralizes and makes 1st layer of Lamellar Bone

-Continues in concentric layers, narrowing tunner forming Osteon with Haversian Canal in Center

-Bone splits, blood vesssels break at fracture

-Clot forms between broken ends

-Causes ischemia and death to bone immediately adjacent to break

-Necrotic bone will be resorbed by osteoclasts

-Neutrophils enter area then macrophages eat RBC's, Fibrin and Necrotic Tissue

-Clot is then slowly removed

-Capillaries and fibroblasts from CT form the Procallus (granulation tissue)

-At same time, cytokines activate Osteoprogenitor cells in periosteum, med. cavity and soft tissues -> stimulate osteoclastic and blastic activity

-Consists of granulation tissue with new bone and cartilage

-Bridges gap between break

-External Callus forms arouns broken ends on external surface

-Internal Callus forms between cortical and medullary surfaces

-Clot invated by OsteoP cells from endosteum and Multipotential cells of bone marrow

-> forms the Internal Callus

Components:

1. New bone trabeculae form in each fragment's Medullary cavity due to Osteogenic Cells. Trabeculae grow and connect

2. New bone Trabeculae form between Cortical bone

-The Collar/Sleeve on outside fragments produced by Periosteal Activity

-Consisted of 3 different zones:

1. First Zone

2. Intermediate Zone

3. Surface Zone

-Closest to outer surface of bone fragment

-Osteogenic cells deposit bone matrix (membrane bone formation)

-New trabeculae are cemented to fragments

-Zone immediately outside Osseous layer

-Osteogenic cells in less vascular environment turn tino Chrondroblasts -> form cartilage

-Proliferating osteogenic layer with rich vascular supply

-Where bone is formed

The 2 collars of bone from each fragment anlarge and fuse -> callus is now a Fusiform mass and Cancellous bone

-Cartilage in external callus replaced by Primary Bone via Endochondral Ossification

-Dead bone is resorbed and replaced by Cancellous bone

-Cancellous bone of Callus is replaced by Dense Cortical bone

-Supporting Trabeculae are resorbed and original structure of bone is restored