Osteoclasts

IVVY535-538

-4 a.a. sequence on cytoplasmic domain of RANK that functions to commit macrophages to osteoclast lineage by priming osteoclast genes for expression -Also interacts with Vav3 indirectly, which in turn modulates the osteoclast cytoskeleton

IL-34

-Alternate ligand to M-CSF, able to support osteoclastogenesis when M-CSF is absent in the presence of RANKL -Possibly expressed under pathologic conditions

Monocyte/Macrophage colony stimulating factor(M-CSF)

-Binds c-Fms, activates downstream pathways that stimulate osteoclast precursor profileration and survival(also differentiation, but not its primary function) -Convert granulocyte/macrophage progenitors(GMPs) to monocyte/macrophage lineage cells -In the bone microenvironment, this signal is secreted by bone marrow stroll cells & osteoblasts -Indirectly exerts an effect on cytoskeletal organization through c-Fms

Syt VII

-Broadly expressed vesicular trafficking protein that regulates calcium-dependent exocytosis of lysosomes in macrophages -Plays essential role in formation of ruffled border, mediating fusion of secretory lysosomal vesicles to bone-opposed membrane in osteoclasts

Hematopoietic

-Cells from bone marrow(mice), spleen, or peripheral blood -Osteoclast precursors

IFN-𝛾

-Inhibits osteoclastogenesis by suppressing osteoclast genes, however, this repressive effect is reduced when bone marrow macrophages(BMMs) are pre-treated with RANKL

Integrin αvß3

-Membrane protein that mediates cytoskeletal organization through its cytoplasmic domain in osteoclasts -Signaled by RGD a.a. sequence in bone matrix proteins -Polarizes resorptive machinery to bone-cell interface, creates resorptive compartment with an actin ring surrounding it -Binding with its signal, this membrane protein's cytoplasmic domain phosphorylates, activating c-Src, recruiting Slp76 & Vav3, eventually leading to the activation of Rac 1/2 which triggers cytoskeletal reorganization

RANKL

-OPGL,ODF, TRANCE -Tumor necrosis factor(TNF) that activates RANK(TNFR), which stimulates a signaling pathway that primes osteoclast genes -Derived from bone marrow stromal(B & T) cells -Regulates later stages of osteoclast differentiation, plays a role in bone remodeling -Downstream

RANK

-RANKL receptor that recruits TRAFs with cytoplasmic domain -Shares no homology with any know TNFR, so may have a unique signaling pathway essential of osteoclastogenesis

Ruffled Border

-Resorptive organelle -Functional form when H⁺-ATPase inserted into plasma membrane and cathespin K are mobilized towards the bone-facing membrane in/on vesicles after signaled by bone matrix. These vesicles are then localized via vesicular exocytosis

Cytokines

-Small secreted proteins that effect surrounding cells -Mediate osteoclast differentiation and function

Osteoprotegrin(OPG)

-Soluble decoy receptor for RANKL, competes with RANK for RANKL -Without this, osteoporosis

c-Fms

-Type III protein tyrosine kinase receptor -Has a ligand binding, transmembrane, and tyrosine kinase domain -Dimerizes with M-CSF induction, which transphosphorylates tyrosine residues, providing docking sites for signaling molecules

Y697/Y974

-Tyrosine residue on c-Fms that recruits Grb2→Sos→Ras→Raf→MEK→ERK -Activates pathway that promotes osteoclast survival and proliferation

Y721

-Tyrosine residue on c-Fms that recruits Pl3K→Akt -Activates pathway that promotes osteoclast survival and proliferation

Y559

-Tyrosine residue on c-Fms that recruits c-Src→Pl3k→akt -Activates pathway that promotes osteoclast survival and proliferation

Bone Remodeling Compartment(BRC)

-Where Osteoclast differentiation must occur, highly vascular compartments covered by bone lining cells -Keeps bone remodeling process confined -Crucial bone remodeling coupling factor

4 Stages of Bone Remodeling

1)Intiation-recruit osteoclast precursors to BRC by Osteocytes 2)Predominant bone resorption period- differentiation of osteoclast precursors & function of osteoclast, concurrent osteoprogenitor recruitment 3)Predominant bone formation period-osteoprogenitor differentiation, function of osteoblast, &osteoid synthesis 4) Mineralization of osteoid, conclusion of bone remodeling

Basic Multicellular Unit(BMU)

4 distinct types of bone- Bone lining cells, Osteocytes, Osteoblasts, and Osteoclasts

Akt, NF-kB, JNK, p38, ERK, NFATc1

6 major signaling pathways which are activated collectively by the 3 TRAF-RANK binding motifs

RGD sequence

Amino acid sequence present in various bone matrix proteins, recognized by integrin αvß3

Granulocyte/Macrophage Colony Stimulating Factor(GM-SCF)

Convert common myeloid progenitors(CMPs) to granulocyte/macrophage progenitors(GMPs) in the bone marrow space

Stem Cell Factor(SCF)/Il-3/Il-6

Convert hematopoietic stem cells(HSCs) to common myeloid progenitors(CMPs) in the bone marrow space

Increased Osteoclast Function

Decline in Estrogen(Post-menopausal), Rheumatoid Arthritis, Osteolytic complications of Tumors(metastatic like breast cancer)

Bicarbonate

Exchanged with chloride ions through the osteoclast's basolateral membrane

Syt

Family of vesicular trafficking proteins that link and target vesicles, varying affinities for calcium and phospholipids

IGF-I & TGF-ß

Growth factors released by bone resorbrion to promote Osteoprogenitor differentiation into osteoblasts and osteoblast survival

Vav3

Guanine nucleotide exchange factor that converts rac-GDP to rac-GTP

Chloride Ions

Ions transported from extracellular space into cell through exchange with bicarbonate, then into the resorption compartment in order to maintain electroneutrality

Cathespin K

Lysosomal proteolytic enzyme responsible for degrading organic component of the bone matrix

Bone

Mechanical support, locomotion & protection(marrow & brain), metabolic organ, maintains mineral homeostasis, regulates energy expenditure

Transcytosis

Mechanism by which osteoclasts rid of the resorbed bone material

H⁺-ATPase

Membrane protein abundant on ruffled border of osteoclasts, transports protons into the resorption compartment, which degrade basic minerals like Calcium

Carbonic Acid

Molecule that provides protons to be secreted into the resorption compartment

Osteocytes

Most abundant bone cell, primary mechanosensing cell, may control initiation of bone remodeling, produces RANKL

Monocytes/Macrophages

Precursors to Osteoclasts

Mesenchymal Cells

Precursors to Osteocytes, Osteoblasts, and Bone lining cells

Hydroxyapatite

Primary inorganic molecule in bone

Type I Collagen

Primary organic molecule in bone

Y559/Y697/Y721

Sequences on c-Fms that for a multimeric signaling protein that exert an effect on cytoskeletal organization

TRAF6

Signal protein associated with RANK intracellular domain motif 1, works with c-SRC to act as the primary motif for osteoclast survival and activation

TNF Receptor Associated Factor(TRAF)

Signal proteins that bind to cytoplasmic domain of RANK

Integrin

Transmembrane proteins that link cytoplasm to extracellular matrix(αvß3 in osteoclasts)