代谢性骨病分子、细胞生物学

Osteoclast formation and activity. Shown centrally is a scheme of osteoclast differentiation in response to M-CSF and RANKL. Above the proposed differentiation pathway are examples of direct inhibitors, whilst below are indirect inhibitors signalling through intermediate cell types.
Osteoblast development and differentiation
组织细胞学基础
Transcription factors Cbfa1/Runx2 + Surface markers STRO-1 SB-10/ALCAM HOP-26/CD63 Enzymes Alkaline phosphatase + 0 +
propagation of calcium wave
Institute of Metabolism & Endocrinology, Central South University
The cadherin adhesion complex.
A single connexin monomer is composed of 4 transmembrane spanning domains (TM1–4), two extracellular loops (EC1,2), and a cytoplasmic loop (CL). A connexon, or hemichannel, is composed of a hexameric array of connexins. When docked with a connexon on an appositional cell membrane, a gap junctional channel is formed which permits the transfer of small molecules such as nucleotides, metabolites, and second messengers among coupled cells.
Institute of Metabolism & Endocrinology, Central South University
Osteoclast development and differentiation
Institute of Metabolism & Endocrinology, Central South University
Cell–cell interactions play an important role in in.uencing and coordinating cell function. Both adherens and communicative junctions can regulate the abundance or movement of signaling molecules or transcriptionally active factors, whose canonical pathways converge upon the nucleus to modulate gene expression and ultimately cellular function.
• Differentiation, activity, and survival signals merge in intracellular second messengers: include cytoplasmic kinases of several
families; differentiation pathways often terminate in Erk/Jun kinases or NF-jB. Key regulatory intermediates include TRAF6, src, Smad3, phosphatidylinositol-3-kinase, Jak/Stat, and the cGMP-dependent protein kinase I. There are substantial uncertainties regarding how intracellular agents connect to primary signals.
The bone remodeling units or bone multicellular units (BMUs)
Institute of Metabolism & Endocrinology, Central South University
骨组织的细胞成份
• 成骨谱系：间充质干细胞，骨源性始组 细胞（osteoprogenitor cells）、成骨细胞 （osteoblast）、骨衬细胞（bone-lining cell）、骨细胞（osteocyte） • 破骨谱系：多潜能造血干细胞、破骨细 胞（osteoclast） • 成软骨细胞、软骨细胞、破软骨细胞
Wnt signaling in osteoblasts and bone diseases
Osteoclast development and differentiation
• Normal differentiation requires: tyrosine kinase- and tumor necrosisfamily receptors, normally fms and RANK. Ligands for these receptors plus unidentifed serum or cell-presented factor(s) are needed for in vitro differentiation, possibly signalling via an immune-like tyrosine kinase acceptor molecule.
requires coordinated cellular activities among osteoblasts, osteocytes, and osteoclasts
• Adherens junctions：cadherins in osteogenesis
• Communicating junctions：Gap junctions
Institute of Metabolism & Endocrinology, Central South University
非细胞成分
• • • • • 胶原 非胶原蛋白 骨矿物质 血管 神经
Institute of Metabolism & Endocrinology, Central South University
Skeletal fragility can result from:
(a) failure to produce a skeleton of optimal mass and strength during growth; (b) excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration of the skeleton; (c) an inadequate formation response to increased resorption during bone remodeling.
Connexin43 ，45， 46，the pore is different Development and maintenance of a differentiated osteoblast phenotype. activation of the ERK signaling cascade
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Effects of Wnt signaling on osseous cells. The canonical Wnt signaling pathway promotes the proliferation, expansion and survival of pre- and immature osteoblasts. Dkks, Sfrps, and Wif-1 antagonize Wnt signaling in osteoblasts to facilitate death of immature cells, but they may also downregulate the pathway in mature cells to induce terminal differentiation.
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Phex Collagen and non-collagenous proteins Collagen type I Osteocalcin ? + -
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