Sizzled Is Unique among Secreted Frizzled-related Proteins for Its Ability to Specifically Inhibit Bone Morphogenetic Protein-1 (BMP-1)/Tolloid-like Proteinases
Abstract:Background: Xenopus and zebrafish BMP-1/tolloid-like proteinases (BTPs) are inhibited by sizzled, a secreted frizzledrelated protein (sFRP) not present in mammals. Results: Xenopus sizzled is a very potent inhibitor of human BTPs, whereas mammalian sFRPs have no effect. Conclusion: Regulation of BTP activity by sFRPs is not conserved in mammals. Significance: Sizzled is the most potent exogenous inhibitor of human BTPs.
“…Although shared by zebrafish [84] and at least one other Xenopus sFRP [85], the transposition of this regulatory mechanism to mammals is a matter of controversy. Among the five mammalian sFRPs, only sFRP-2 has been reported to affect BTP activity and the results are highly contradictory, including inhibition [83,86], activation [87] or no effect [38,88]. These discrepancies probably reflect the high context-dependence of this regulation and/or the existence of multiple conformational states for sFRPs.…”
Bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases, here called BTPs, include the proteases originally identified for their roles in the C-terminal maturation of fibrillar procollagens ("procollagen C-proteinase"). Though numerous other substrates have since been discovered, the BTPs remain the main proteases involved in extracellular matrix assembly with little or no implication in matrix degradation. During the same period however, the BTPs have also become established as important proteases in the activation of growth factors, including TGF-β1, BMP-2/-4, GDF-8/-11 and IGFs, as well as the release of anti-angiogenic fragments from parent proteins. The BTPs are therefore key players in many pathophysiological processes such as morphogenesis, tissue repair and tumor progression. This mini-review summarizes our current knowledge of the functions of BTPs, their substrates and unusual mechanisms of regulation, and discusses their potential as new targets for future therapies.
“…Although shared by zebrafish [84] and at least one other Xenopus sFRP [85], the transposition of this regulatory mechanism to mammals is a matter of controversy. Among the five mammalian sFRPs, only sFRP-2 has been reported to affect BTP activity and the results are highly contradictory, including inhibition [83,86], activation [87] or no effect [38,88]. These discrepancies probably reflect the high context-dependence of this regulation and/or the existence of multiple conformational states for sFRPs.…”
Bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases, here called BTPs, include the proteases originally identified for their roles in the C-terminal maturation of fibrillar procollagens ("procollagen C-proteinase"). Though numerous other substrates have since been discovered, the BTPs remain the main proteases involved in extracellular matrix assembly with little or no implication in matrix degradation. During the same period however, the BTPs have also become established as important proteases in the activation of growth factors, including TGF-β1, BMP-2/-4, GDF-8/-11 and IGFs, as well as the release of anti-angiogenic fragments from parent proteins. The BTPs are therefore key players in many pathophysiological processes such as morphogenesis, tissue repair and tumor progression. This mini-review summarizes our current knowledge of the functions of BTPs, their substrates and unusual mechanisms of regulation, and discusses their potential as new targets for future therapies.
“…5A, second cluster from top). Down-regulated BMP antagonists include Gremlin1 and Chordin (27,28), and down-regulated Wnt antagonists include Dikkopf1 (Dkk1), Secreted frizzled-related protein (Sfrp)-4, Sfrp5, and Wnt inhibitory factor 1 (Wif1) (29)(30)(31).…”
The postnatal skeleton undergoes growth, remodeling, and repair. We hypothesized that skeletal progenitor cells active during these disparate phases are genetically and phenotypically distinct. We identified a highly potent regenerative cell type that we term the fracture-induced bone, cartilage, stromal progenitor (f-BCSP) in the fracture callus of adult mice. The f-BCSP possesses significantly enhanced skeletogenic potential compared with BCSPs harvested from uninjured bone. It also recapitulates many gene expression patterns involved in perinatal skeletogenesis. Our results indicate that the skeletal progenitor population is functionally stratified, containing distinct subsets responsible for growth, regeneration, and repair. Furthermore, our findings suggest that injury-induced changes to the skeletal stem and progenitor microenvironments could activate these cells and enhance their regenerative potential.osteogenesis | skeletal stem/progenitor cell | fracture healing | regeneration | injury activation
“…4). Additionally, sFRP2 may only affect the activity of BMP1 on type I collagen, but not for type III collagens [38]. It is well known that PCPE1 can enhance the pCP activity of BMP1, but there still exists a debate about whether the pCP activity of BMP1 is inhibited or enhanced by sFRP2 [35].…”
This article corrects: Synergistic effect of PCPE1 and sFRP2 on the processing of procollagens via BMP1, Volume 593, Issue 1, 119–127. Article first published 09 November 2018. https://doi.org/10.1002/1873-3468.13291
Dr Daniel S. Greenspan was inadvertently omitted from the list of authors in the original publication. The correct list of authors is as shown above.
Dr Daniel S. Greenspan affiliation and contact details are as follows:
Department of Cell and Regenerative Biology, University of Wisconsin, Room 4503, WIMRII, 1111 Highland Ave, Madison, WI 53705, dsgreens@wisc.edu
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