Bone Development Repair

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Osteogenesis Two Processes

Intramembranous Bone tissue is formed

directly in primitive connective tissue(mesencyhme).Endochondral Bone tissue replaces a

hyaline cartilage template.


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Regulation of Mesenchymal CellDifferentiation and Skeletal PatterningMesenchymal cell differentiation into osteoblasts regulatedby Core Binding Factor-a1 (CBFA1)/RUNX2; differentiationinto chondrocytes regulated by SOX9.

Skeletal patterning controlled by a multitude of signalingmolecules and transcription factors, including wnt andhedgehog signaling factors, homeobox (HOX) transcriptionfactors, members of the transforming growth factor-

TGF and fibroblast growth factor (FGF) families.

For limb morphogenesis, wnt7a is important fordorsal/ventral patterning, FGF4 for proximal/distalpatterning, and sonic hedgehog for posterior/anteriorpatterning.


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Intramembranous Bone Formation


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Intramembranous Bone Formation


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Endochondral Bone Formation


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Steps in endochondralbone formation leadfrom mesenchymalcondensations tocartilage synthesis,chondrocytedifferentiation anddeath, and

replacement by bone.

From mesenchymal condensation to

hyaline cartilage model


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Chondrocytehypertrophy

Cartilagemineralizes

Replacedby bone


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Endochondral Ossification


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Local Regulators of EndochondrOssification

Indian hedgehog (Ihh) protein isproduced by proliferatingchondrocytes; stimulates thesynthesis and secretion ofparathryroid hormone relatedprotein (PTH-RP) and regulatesformation of the periosteal bonecollar.

PTH-RP stimulates chondrocyteproliferation and inhibits theirdifferentiation into hypertrophicchondrocytes.

Hypertrophic chondrocytessecrete type X collagen, a markerof terminal differentiation andvascular endothelial growth factor(VEGF), an inducer of vascularinvasion.

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Aberrant Regulation ofEndochondral Ossification

Example ofconsequencescaused when agrowth factorimportant forregulation of

endochondralbone formationis functionallyinactivated.


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Joints


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Definition

Articulations: The site where 2 or more bonesmeet

Joints are the weakest part of the skeleton


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Synovial Joints

Articulating bones are separated bya fluid-containing joint cavity

Synovial (Diarthrosis/True joints) :Unite two bone ends covered by articularcartilage

Surrounded by a thick articular capsuleExamples: appendicular skeleton andvertebral joints


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Structure of Synovial JointsArticular CartilageSynovial (joint) cavity

Articular Capsule

Two layers around cavity

Outer fibrous continuous with periosteumInner synovial

Synovial FluidDerived from filtration through the capillaries andfills the space of the capsuleViscousIt consists of hyaluronic acid and functions as a lubricant

Reinforcing Ligaments

Some have fatty Pads or articular Discs


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Synovial Joints


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Panus

Rheumatoid Arthritis


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Mechanism of Rheumatoid Arthritis


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Erosive Arthritis Develops in theComplete Absence of TNF

TNF-deficient mice with SCW-induced arthritis

SCW = streptococcal cell wallvan den Berg W. Semin Arthritis Rheum. 2001;30(suppl 2):7-16.


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Control mice with SCW-induced arthritis

IL-1 -deficient mice withSCW-induced arthritis

IL-1 Mediates the Development ofErosive Disease

SCW = streptococcal cell wallvan den Berg W. Semin Arthritis Rheum. 2001;30(suppl 2):7-16.


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RANKL, OPG: Key Components of BoneErosion

Bone erosion is mediated by activated osteoclastsOsteoprotegerin ligand (RANKL): induces osteoclast differentiation is crucial for osteoclast activation

is identical to receptor activator of NF- B ligand(RANK-L)

is identical to osteoclast differentiating factorOsteoprotegerin (OPG) binds RANKL, thus inhibitingbone resorptionRANKL/OPG balance determines relative degree oferosion


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Regulation of Osteoclast Differentiation by OsteoblastsM-CSF:Macrophages colony

stimulating factorRANK:Receptor for activationof nuclear factor kappa B

RANKL: Receptorfor activation of nuclearfactor kappa B ligand


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Fracture Repair


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Inflammatory Phase


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Repair Phase


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Remodeling Phase


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Factors Influencing the Rate ofFracture Healing

Local FactorsSeverity of Trauma

Blood SupplyMobilityInfection

Disease

Systemic FactorsHormones

NutritionDisease

Bone Development Repair

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