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Cited by 58Osteoarthritis Treatment and MechanismsProtease and Inhibitor MechanismsBone Metabolism and Diseases

SOST/Sclerostin improves posttraumatic osteoarthritis and inhibits MMP2/3 expression after injury

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Chang, Jiun C, Christiansen, Blaine A, Murugesh, Deepa K, Sebastian, Aimy, Hum, Nicholas R, Collette, Nicole M, Hatsell, Sarah, Economides, Aris N +2 more·2018·Journal of Bone and Mineral Research
DOI 10.1002/jbmr.3397PMC PMC6033030
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Abstract

Patients with anterior cruciate ligament (ACL) rupture are two times as likely to develop posttraumatic osteoarthritis (PTOA). Annually, there are ∼900,000 knee injuries in the United States, which account for ∼12% of all osteoarthritis (OA) cases. PTOA leads to reduced physical activity, deconditioning of the musculoskeletal system, and in severe cases requires joint replacement to restore function. Therefore, treatments that would prevent cartilage degradation post-injury would provide attractive alternatives to surgery. Sclerostin (Sost), a Wnt antagonist and a potent negative regulator of bone formation, has recently been implicated in regulating chondrocyte function in OA. To determine whether elevated levels of Sost play a protective role in PTOA, we examined the progression of OA using a noninvasive tibial compression overload model in SOST transgenic (SOSTTG) and knockout (Sost-/-) mice. Here we report that SOSTTG mice develop moderate OA and display significantly less advanced PTOA phenotype at 16 weeks post-injury compared with wild-type (WT) controls and Sost-/-. In addition, SOSTTG built ∼50% and ∼65% less osteophyte volume than WT and Sost-/-, respectively. Quantification of metalloproteinase (MMP) activity showed that SOSTTG had ∼2-fold less MMP activation than WT or Sost-/-, and this was supported by a significant reduction in MMP2/3 protein levels, suggesting that elevated levels of SOST inhibit the activity of proteolytic enzymes known to degrade articular cartilage matrix. Furthermore, intra-articular administration of recombinant Sost protein, immediately post-injury, also significantly decreased MMP activity levels relative to PBS-treated controls, and Sost activation in response to injury was TNFα and NF-κB dependent. These results provide in vivo evidence that sclerostin functions as a protective molecule immediately after joint injury to prevent cartilage degradation. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

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  • In experimental animals, sclerostin generated in response to TNF-α and IL-1β improves post-traumatic osteoarthritis by inhibiting the activity of proteolytic enzymes involved in cartilage degradation.

    “sclerostin generated in response to TNF-α and IL-1β improves post-traumatic osteoarthritis by inhibiting the activity of proteolytic enzymes involved in cartilage degradation [75]”

    From Osteoclasts and Microgravity (2020) · cites this paper as [75]

    The Results report that TNFα-dependent Sost activation occurs in injured mouse joints, and the Discussion says elevated sclerostin reduces the expression and activity of cartilage-degrading MMP2/3 after injury. The Discussion proposes a role for IL1 generally but specifically mentions evidence for IL1α, not IL-1β; the claim’s identification of IL-1β as a trigger is therefore unsupported by our copy (page numbers unavailable). (LLM, conf=0.87)

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Authors
Chang, J. C., Christiansen, B. A., Murugesh, D. K., Sebastian, A., Hum, N. R., Collette, N. M., Hatsell, S., Economides, A. N., Blanchette, C. D., & Loots, G. G.
Affiliations
  • Lawrence Livermore National Laboratory (US)
  • University of California Davis Medical CenterSacramentoCAUSA
  • Regeneron (United States) (US)
Corresponding author
Loots, Gabriela G
ORCID
Venue
Journal of Bone and Mineral Research
Publisher
Oxford University Press (OUP)
Published
2018-01-26
Volume
33
Issue
6
Pages
1105-1113
ISSN
  • 0884-0431 (ISSN-L)
  • 1523-4681
DOI
10.1002/jbmr.3397
PMC
PMC6033030
OpenAlex
W2792116008
Cited by
58
References
3
Citations by year
2026: 5 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 6 · 2020: 9 · 2019: 3 · 2018: 6
FWCI
5.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Bone and Mineral Research (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Keywords
sclerostin, post-traumatic osteoarthritis, anterior cruciate ligament rupture, MMP-2, matrix metalloproteinase-3, articular cartilage degeneration, osteophytes, Wnt signaling, TNF-α, NF-κB, chondroprotection, knee injury
MeSH terms
Anterior Cruciate Ligament Injuries, Animals, Binding Sites, Extracellular Matrix, Genetic Markers, Glycoproteins, Humans, Mice, Inbred C57BL, Models, Biological, Phenotype, Recombinant Proteins, Tumor Necrosis Factor-alpha, Up-Regulation, NF-kappa B, Matrix Metalloproteinase 3, Bone Morphogenetic Proteins, Osteoarthritis, Knee, Matrix Metalloproteinase 2, Intercellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Osteophyte

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