Site-1 protease is essential for endochondral bone formation in mice

Patra, Debabrata; Davies, Sherri R.; Bryan, J.; Franz, Carl; Hunziker, Ernst B.; Sandell, Linda J.

doi:10.1084/jem20412oia28

Cited by 16 publications

(25 citation statements)

References 50 publications

(66 reference statements)

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“…However, if such high pressures would arise, they would likely be detrimental to the cell. Indeed, S1Pcko mice show severe intracellular changes, exemplified by severely disrupted endoplasmic reticulum and a pathological fat-metabolism (Patra et al 2007). However, causality remains speculative.…”

Section: Discussionmentioning

confidence: 99%

Mechanics of chondrocyte hypertrophy

Donkelaar

Wilson

2011

Biomech Model Mechanobiol

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Chondrocyte hypertrophy is a characteristic of osteoarthritis and dominates bone growth. Intra-and extracellular changes that are known to be induced by metabolically active hypertrophic chondrocytes are known to contribute to hypertrophy. However, it is unknown to which extent these mechanical conditions together can be held responsible for the total magnitude of hypertrophy. The present paper aims to provide a quantitative, mechanically sound answer to that question. To address this aim requires a quantitative tool that captures the mechanical effects of collagen and proteoglycans, allows temporal changes in tissue composition, and can compute cell and tissue deformations. These requirements are met in our numerical model that is validated for articular cartilage mechanics, which we apply to quantitatively explain a range of experimental observations related to hypertrophy. After validating the numerical approach for studying hypertrophy, the model is applied to evaluate the direct mechanical effects of axial tension and compression on hypertrophy (Hueter-Volkmann principle) and to explore why hypertrophy is reduced in case of partially or fully compromised proteoglycan expression. Finally, a mechanical explanation is provided for the observation that chondrocytes do not hypertrophy when enzymatical collagen degradation is prohibited (S1Pcko knock-out mouse model). This paper shows that matrix turnover by metabolically active chondrocytes, together with externally applied mechanical conditions, can explain quantitatively the volumetric change of chondrocytes during hypertrophy. It provides a mechanistic explanation for the observation that collagen degradation results in chondrocyte hypertrophy, both under physiological and pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Mechanics of chondrocyte hypertrophy

Donkelaar

Wilson

2011

Biomech Model Mechanobiol

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“…Mbtps1-floxed mice were obtained from Dr. Jay Horton, Southwest Medical School and Dr. Linda Sandell, Washington University (18,19); Dmp1-cre mice were obtained from Dr. Lynda Bonewald, University of Missouri-Kansas City (15). Males (Mbtps1(flx/ϩ):Dmp1(cre/ ϩ)) were crossed with females (Mbtps1(flx/flx)) to obtain Mbtps1 cKO mice (Mbtps1(flx/flx):Dmp1(cre/ϩ)) offspring; this strategy deletes exon 2 of the Mbtps1 gene and should be effective in ablating expression of all expressed forms containing the catalytic site (18).…”

Section: Methodsmentioning

confidence: 99%

Deletion of Mbtps1 (Pcsk8, S1p, Ski-1) Gene in Osteocytes Stimulates Soleus Muscle Regeneration and Increased Size and Contractile Force with Age

Gorski

Huffman

Vallejo³

et al. 2016

Journal of Biological Chemistry

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Conditional deletion of Mbtps1 (cKO) protease in bone osteocytes leads to an age-related increase in mass (12%) and in contractile force (30%) in adult slow twitch soleus muscles (SOL) with no effect on fast twitch extensor digitorum longus muscles. Surprisingly, bone from 10 -12-month-old cKO animals was indistinguishable from controls in size, density, and morphology except for a 25% increase in stiffness. cKO SOL exhibited increased expression of Pax7, Myog, Myod1, Notch, and Myh3 and 6-fold more centralized nuclei, characteristics of postnatal regenerating muscle, but only in type I myosin heavy chain-expressing cells. Increased expression of gene pathways mediating EGF receptor signaling, circadian exercise, striated muscle contraction, and lipid and carbohydrate oxidative metabolism were also observed in cKO SOL. This muscle phenotype was not observed in 3-month-old mice. Although Mbtps1 mRNA and protein expression was reduced in cKO bone osteocytes, no differences in Mbtps1 or cre recombinase expression were observed in cKO SOL, explaining this age-related phenotype. Understanding bone-muscle cross-talk may provide a fresh and novel approach to prevention and treatment of age-related muscle loss.Bone osteocytes are multifunctional endocrine cells. Osteoid osteocytes control bone mineralization by secretion of DMP1, phosphate-regulating endopeptidase homolog, X-linked (PHEX), and matrix extracellular phosphoglycoprotein (MEPE) (1), whereas mature osteocytes secrete sclerostin, an inhibitor of bone formation, and regulate phosphate homeostasis and, indirectly, bone mineralization via production of FGF23 (2). Osteocytes are the mechanosensory cells in bone and appear to regulate muscle function and myogenesis (3-5). Specifically, deletion of connexin43 in osteoblasts/osteocytes shows it is involved in postnatal bone-muscle cross-talk via an osteocalcin-mediated stimulation of muscle formation and function (5). Differentiated muscle cells, in return, secrete as yet unidentified factors that protect osteocytes against apoptosis and produce a factor that synergizes with fluid flow shear stress to increase prostaglandin E 2 production by osteocytes (6). Myogenesis in adult muscle occurs via activation of satellite (stem) cells during muscle regeneration after injury or exercise-induced damage (7,8). Distinct populations of satellite cells appear to be responsible for regeneration of fast twitch and slow twitch myofibers (9, 10), respectively. MBTPS1 (SKI-1, PCSK8, S1P) 3 is the eighth member of the proprotein convertase family of proteases (11). Localized to the cis/medial Golgi, MBTPS1 catalyzes the mandatory first cleavage of transmembrane-bound transcription factors like SREBP1 and cAMP-response element-binding protein; once released, their DNA binding domains are imported into the nucleus where they regulate transcription (12). Interestingly, MBTPS1 is required for the transcription of a number of bone matrix and mineralization-related genes including type XI collagen, Phex, Dmp1, fibronectin, and fibrillin ...

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“…S6) at E16.5. Our previous studies had demonstrated that S1P ablation in the chondrocyte lineage resulted in intracellular Col II entrapment with abnormal cartilage that impeded endochondral bone development (Patra et al, 2014a(Patra et al, , 2007. However, S1P-ablation in the Osx lineage results in cartilage matrix very similar to WT.…”

Section: S1p Ablation In the Osx Lineage Delays Endochondral Bone Devmentioning

confidence: 99%

“…S1P ablation in osteochondroprogenitors in mice (S1P cko ; via Col2-Cre) results in chondrodysplasia (Patra et al, 2014b(Patra et al, , 2007. These mice show abnormal cartilage development with type IIB procollagen ( pro-Col IIB) entrapment in the chondrocyte ER and a drastic reduction in type II collagen (Col II) protein in the cartilage.…”

Section: Introductionmentioning

confidence: 99%

Site-1 protease regulates skeletal stem cell population and osteogenic differentiation in mice

Patra

Mueller

Sandell

2017

Osteoarthritis and Cartilage

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Site-1 protease (S1P) is a proprotein convertase with essential functions in the conversion of precursor proteins to their active form.In earlier studies, we demonstrated that S1P ablation in the chondrocyte lineage results in a drastic reduction in endochondral bone formation. To investigate the mechanistic contribution of S1P to bone development we ablated S1P in the osterix lineage in mice. S1P ablation in this lineage results in osteochondrodysplasia and variable degrees of early postnatal scoliosis. Embryonically, even though Runx2 and osterix expression are normal, S1P ablation results in a delay in vascular invasion and endochondral bone development. Mice appear normal when born, but by day 7 display pronounced dwarfism with fragile bones that exhibit significantly reduced mineral density, mineral apposition rate, bone formation rate and reduced osteoblasts indicating severe osteopenia. Mice suffer from a drastic reduction in bone marrow mesenchymal progenitors as analyzed by colony-forming unit-fibroblast assay. Fluorescence-activated cell sorting analysis of the skeletal mesenchyme harvested from bone marrow and collagenase-digested bone show a drastic reduction in hematopoietic lineage-negative, endothelial-negative, CD105+ skeletal stem cells. Bone marrow mesenchymal progenitors are unable to differentiate into osteoblasts in vitro, with no effect on adipogenic differentiation. Postnatal mice have smaller growth plates with reduced hypertrophic zone. Thus, S1P controls bone development directly by regulating the skeletal progenitor population and their differentiation into osteoblasts.This article has an associated First Person interview with the first author of the paper.

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Site-1 protease is essential for endochondral bone formation in mice

Cited by 16 publications

References 50 publications

Mechanics of chondrocyte hypertrophy

Mechanics of chondrocyte hypertrophy

Deletion of Mbtps1 (Pcsk8, S1p, Ski-1) Gene in Osteocytes Stimulates Soleus Muscle Regeneration and Increased Size and Contractile Force with Age

Site-1 protease regulates skeletal stem cell population and osteogenic differentiation in mice

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