Osteoblasts Origin derived from undifferentiated mesenchymal cells mesenchymal cells then differentiate into osteoprogenitor cells Structure contain increased amounts of endoplasmic reticulum, Golgi apparatus, and mitochondria than other cells allows for synthesis and secretion of bone matrix Function form bone by producing non-mineralized matrix alkaline phosphatase type I collagen osteonectin osteocalcin stimulated by 1,25 dihydroxyvitamin D regulate osteoclast function Signaling osteoblastic differentiation BMP stimulates mesenchymal cells to become osteoprogenitor cells core binding factor alpha-1 (cbf alpha -1: RUNX2) stable beta-catenin plays a major role in inducing cells to form osteoblasts with resulting intramembranous bone formation platelet derived growth factor (PDGF) induces osteoblast differentiation insulin derived growth factor (IDGF) induces osteoblast differentiation osteoblast bone production PTH receptor stimulates alkaline phosphatase and type I collagen production 1,25 dihydroxyvitamin D receptor stimulates matrix and alkaline phosphatase synthesis production of bone specific proteins (osteocalcin) estrogen inhibits bone resorption and stimulates bone production by inhibiting adenylyl cyclase glucocorticoids inhibit collagen and bone matrix production prostaglandins stimulate bone resorption by activating adenylyl cyclase osteoclast signaling interconnected signaling allows coupling of bone resorption and formation osteoclast activation PTH receptors on osteoblast bind to PTH which when leads to expression of RANKL RANKL binds to RANK receptor on osteoclast and bone resorption osteoclast inhibition osteoblasts can secrete OPG (osteoprotegrin) OPG binds to RANKL on the osteoblast, preventing RANK activation inhibits osteoclast activity regulation of hematopoietic cells and immune response occurs through the Jagged1-Notch pathway PTH induces Jagged1 on osteoblasts Jagged1 stimulates Notch receptors on the membrane of hematopoietic stem cells which results in cell proliferation Location more metabolically active cells at the bone surface less active cells in more central bone activated by disruption of the more peripheral osteoblasts Osteoclasts Function reabsorb bone osteoblasts regulate osteoclast bone reabsorbtion (see above) steps in resorption cycle migration to resorption site bone attachment polarization (formation of membrane domains) dissolution of hydroxyapatite degradation of organic matrix removal of degradation products from resorption lacuna apoptosis of the osteoclasts or return to the non-resorbing stage. Origin originate from myeloid hematopoietic cells from monocyte/macrophage cell lineage monocyte progenitors fuse together to form mature multinuclear cells Cellular biology cellular anatomy multinucleated giant cells cellular physiology bone reabsorbtion occurs at ruffled border Howship's lacunae are site of bone resorption where ruffled border meets bone surface tartrate-resistant acid phosphatase secreted by osteoclasts to lowers the Ph (utilizing carbonic anhydrase) and increases the solubility of hydroxyapatite crystals deficiency of carbonic anhydrase prevents bone resorption proteolytic digestion the organic matrix is then removed by proteolytic digestion cathepsin K is one major proteolytic enzyme that degests organic matrix at ruffled border bisphosphonates mechanism prevents osteoclasts from forming ruffled border and producing acid hydrolases Molecular biology osteoclast-bone attachment osteoclast attaches to bone matrix at sealing zone attach to bone surfaces via integrins on osteoclast surface integrins include αVβ3, αVβ5, α2β1, αVβ1 αVβ3 (on osteoclast) is a receptor for vitronectin (on bone surface) Arg-Gly-Asp (RGD) sequence of extracellular bone proteins directly allows binding to integrins antibodies to αVβ3 and RGD inhibit bone resorption osteoclast polarization contain specialized membrane domains ruffled border (RB) functional secretory domain (FSD) basolateral membrane (BL) mineralized bone matrix degradation hydroxyapatite crystals dissolved by HCl secreted through ruffled border into resorption lacuna (RL) RL is an extracelllular space between RB and bone matrix, sealed from ECF by sealing zone uses ATP-consuming proton pumps in RB and in intracellular vacuoles H+ come from carbonic anhydrase II RB has high number of chloride channels (maintain electroneutrality) organic bone matrix degradation lysosomal cysteine proteinases matrix metaloproteinases (MMPs), esp MMP-9 cathepsin K mutation in cathepsin K gene leads to pycnodysostosis removal of degradation products by transcystosis to FSD, where they are secreted into ECF tartrate-resistant acid phosphatase (TRAP) is localized in transcytotic vesicles, generates reactive O2 species that destroys collagen osteoclast-osteoblast signaling osteoblasts upregulate and downregulate osteoclast activity osteoclast activation RANKL (NF-kB ligand) expressed by osteoblasts and tumor cells to activate osteoclasts IL-1 found adjacent to loose total joint implants and known to activate osteoclasts osteoclast inhibition calcitonin IL-10 Osteocytes Origin are former osteoblasts trapped in the matrix they produced account for 90% of cells in the mature skeleton Structure high nucleus to cytoplasm ratio have long cellular processes which communicate with other cells via canalculi in the bone Function maintain bone and cellular matrix important in regulation of calcium and phosphorous concentrations in bone do not express alkaline phosphatase Signaling stimulated by calcitonin inhibited by PTH communicate with adjacent osteocytes via gap junctions in canaliculi Osteoprogenitor Cells Origin originate from mesenchymal stem cells environment will determine their function Function become osteoblasts under low strain and high oxygen tension become cartilage under intermediate strain and low oxygen tension become fibrous tissue under high strain