Membrane trafficking in osteoblasts and osteoclasts: new avenues for understanding and treating skeletal diseases - PubMed (original) (raw)

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Membrane trafficking in osteoblasts and osteoclasts: new avenues for understanding and treating skeletal diseases

Haibo Zhao. Traffic. 2012 Oct.

Abstract

The endocytic and exocytic/secretory pathways are two major intracellular membrane trafficking routes that regulate numerous cellular functions in a variety of cell types. Osteoblasts and osteoclasts, two major bone cells responsible for bone remodeling and homeostasis, are no exceptions. During the past few years, emerging evidence has pinpointed a critical role for endocytic and secretory pathways in osteoblast and osteoclast differentiation and function. The endosomal membrane provides a platform to integrate bone tropic signals of hormones and growth factors in osteoblasts. In osteoclasts, endocytosis, followed by transcytosis, of degraded bone matrix promotes bone resorption. Secretory pathways, especially lysosome secretion, not only participate in bone matrix deposition by osteoblasts and degradation of mineralized bone matrix by osteoclasts; they may also be involved in the coupling of bone resorption and bone formation during bone remodeling. More importantly, mutations in genes encoding regulatory factors within the endocytic and secretory pathways have been identified as causes for bone diseases. Identification of the molecular mechanisms of these genes in bone cells may provide new therapeutic targets for skeletal disorders.

© 2012 John Wiley & Sons A/S.

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Figures

Figure 1

Figure 1. A schematic illustration of bone-remodeling process

Bone surface is covered by lining cells. Osteocytes are the most abundant and long-lived bone cells. They are derived from osteoblasts that have embedded in lacunae in the bone matrix that they secrete. Osteocytes sense mechanical signals and/or micro-damages in bone, thereby sending signals to osteoclasts to initiate bone resorption, which is followed by bone matrix deposition by osteoblasts. Osteoblasts eventually become bone lining cells or osteocytes.

Figure 2

Figure 2. Endocytic and secretory pathways in osteoblasts

In addition to binding to PTH receptor (PTH1R), PTH has been recently shown to induce the endocytosis of TGF-β receptor II (TβRII) and PTH1R into early endosomes (EE), which attenuates the cognate signaling pathways of both receptors. OASIS is an endoplasmic reticulum (ER)-residing transcription factor of CREB/ATF family. It is truncated and translocated into the nucleus to promote type I collage expression in response to ER stress. Opt, osteopotentia, is a newly identified protein that regulates ER volume during osteoblast activation. Sec23, FGD1, and SCYL1BP1/Gorab in red color are proteins mutated in human genetic skeleton diseases. They regulate bone matrix secretion at ER and Golgi, respectively. RANKL, an osteoclast differentiation cytokine, is released from osteoblast secretory lysosomes (SL) regulated by Vps33 and Rab27.

Figure 3

Figure 3. Major intracellular vesicular trafficking pathways in resorbing osteoclasts

The plasma membrane of a resorbing osteoclast is highly polarized. It has four distinct domains: the functional secretory domain (FSD), the free membrane domain (FM), the sealing zone (SZ), and the ruffled border (RB). Six intracellular membrane trafficking pathways have been identified in resorbing osteoclasts so far (they are numbered in the sequence of their appearance in the text). Route 1 is the transcytotic pathway in which type I collagen (type I-Col), active TGF-β, and undercarboxylated osteocalcin (GLU-OCN), an active form of osteocalcin, are transported from the resorption lacunae (RL) to FSD. A fraction of active TGF-β and GLU-OCN are also released from a previous RL when osteoclast migrates to a new resorption site. GLA-OCN (γ-carboxylated osteocalcin) is the mature form of osteocalcin, which is stored in the bone matrix. Route 2 represents a trafficking pathway from the FM to the RB, which has been revealed by transferrin (Tf) and transferrin receptor (TfR). Route 3 and 4 are post-Golgi constitutive secretory pathways that connect Golgi to FM and FSD, respectively. The two pathways can be traced by virus envelop proteins, haemagglutinin (HA) and vesicular stomatitis virus G-protein (VSV-G). Route 5 is a secretory lysosome pathway which delivers cathepsin K (CTSK) and HCl to RL. This pathway is regulated by Rab7 and Plekhm1. The fusion of secretory lysosomes with RB is mediated by tetanus neurotoxin-insensitive vesicular-associated membrane protein (TI-VAMP), Syntaxin 4, and Synaptotagmin VII. Route 6 is a post-Golgi non-lysosomal vesicular pathway which is regulated by Rab3D and is also functional important for the ruffled border formation and bone resorption.

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