SLPI is a novel bone-coupling factor that controls parathyroid hormone-induced bone formation
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ABSTRACT:
PROVIDER: PRJNA607261 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11100958.fastq.gz | Fastqsanger.gz | |||
| SRR11100959.fastq.gz | Fastqsanger.gz | |||
| SRR11100960.fastq.gz | Fastqsanger.gz | |||
| SRR11100961.fastq.gz | Fastqsanger.gz | |||
| SRR11100962.fastq.gz | Fastqsanger.gz |
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Project description:Osteoclastic bone resorption and osteoblastic bone formation/replenishment are closely coupled in bone metabolism. Anabolic parathyroid hormone (PTH), which is commonly used for treating osteoporosis, shifts the balance from osteoclastic to osteoblastic, although the mechanisms underlying this phenomenon are unclear. Here we identified a serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), as a novel coupling factor that is involved in the PTH-mediated shift to the osteoblastic phase. SLPI was highly upregulated in osteoblasts by PTH, and genetic ablation of SLPI severely impaired PTH-induced bone formation. SLPI induction in osteoblasts enhanced osteoblast differentiation intracellularly and was also secreted extracellularly, attracting neighboring osteoclasts to suppress osteoclastic function. Intravital bone imaging revealed that the PTH-mediated association between osteoblasts and osteoclasts was disrupted in the absence of SLPI. Collectively, these results demonstrate that SLPI, a previously unrecognized bone-coupling factor, mediates the communication of osteoblasts with osteoclasts to promote PTH-induced bone formation.
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Project description:The effect of parathyroid hormone (PTH) analog treatment was tested on osteoblasts prepared from calvaria of C57BL/6J mice 7-10 days old. Osteoblasts were treated for 4 hr with either human parathyroid hormone (1-34) (hPTH(1-34), bovine (D-Trp12,Tyr34)-PTH(7-34) amide (bPTH(7-34)), bPTH(3-34), hPTH(1-31), or hPTH(7-34). Gene expression effects were evaluated by DNA microarray.
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Project description:Peptide ligands of class B GPCRs act via a two step binding process, but many gaps remain in our understanding of the essential mechanisms that link the extracellular binding of peptide ligands to intracellular receptor arrestin interaction. Using NMR, crosslinking coupled to mass spectrometry, signaling experiments, and computational approaches on the parathyroid hormone (PTH) type 1 receptor (PTHR), we show that the initial binding of the PTH C terminal part to the receptor constrains the conformation of the flexible N terminal signaling epitope of the PTH before a second binding event takes place. A hot spot PTH residue, His9, that inserts into the transmembrane domain of the PTHR at this second step allosterically engages receptor and arrestin coupling. The mechanism appears to elicit a conformational change in the receptor intracellular loop 3 (ICL3) that permits favorable interactions with the b arrestin finger loop. These results unveil structural determinants for PTHR arrestin complex formation and reveal that the two step binding mechanism proceeds via cooperative fluctuations between the peptide ligand and the receptor, which may be extended to other class B GPCRs.
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Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity.
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