Teriparatide ameliorates articular cartilage degradation and aberrant subchondral bone remodeling in DMM mice

Journal of Orthopaedic TranslationVolume 38, January 2023, Pages 241-255Journal of Orthopaedic TranslationAuthor links open overlay panelAbstractObjective

Knee osteoarthritis (KOA) is a highly prevalent musculoskeletal disorder characterized by degeneration of cartilage and abnormal remodeling of subchondral bone (SCB). Teriparatide (PTH (1–34)) is an effective anabolic drug for osteoporosis (OP) and regulates osteoprotegerin (OPG)/receptor activator of nuclear factor ligand (RANKL)/RANK signaling, which also has a therapeutic effect on KOA by ameliorating cartilage degradation and inhibiting aberrant remodeling of SCB. However, the mechanisms of PTH (1–34) in treating KOA are still uncertain and remain to be explored. Therefore, we compared the effect of PTH (1–34) on the post-traumatic KOA mouse model to explore the potential therapeutic effect and mechanisms.

Methods

In vivo study, eight-week-old male mice including wild-type (WT) (n ​= ​54) and OPG−/− (n ​= ​54) were investigated and compared. Post-traumatic KOA model was created by destabilization of medial meniscus (DMM). WT mice were randomly assigned into three groups: the sham group (WT-sham; n ​= ​18), the DMM group (WT-DMM; n ​= ​18), and the PTH (1–34)-treated group (WT-DMM ​+ ​PTH (1–34); n ​= ​18). Similarly, the OPG−/− mice were randomly allocated into three groups as well. The designed mice were executed at the 4th, 8th, and 12th weeks to evaluate KOA progression. To further explore the chondro-protective of PTH (1–34), the ATDC5 chondrocytes were stimulated with different concentrations of PTH (1–34) in vitro.

Results

Compared with the WT-sham mice, significant wear of cartilage in terms of reduced cartilage thickness and glycosaminoglycan (GAG) loss was detected in the WT-DMM mice. PTH (1–34) exhibited cartilage-protective by alleviating wear, retaining the thickness and GAG contents. Moreover, the deterioration of the SCB was alleviated and the expression of PTH1R/OPG/RANKL/RANK were found to increase after PTH (1–34) treatment. Among the OPG−/− mice, the cartilage of the DMM mice displayed typical KOA change with higher OARSI score and thinner cartilage. The damage of the cartilage was alleviated but the abnormal remodeling of SCB didn't show any response to the PTH (1–34) treatment. Compared with the WT-DMM mice, the OPG−/−-DMM mice caught more aggressive KOA with thinner cartilage, sever cartilage damage, and more abnormal remodeling of SCB. Moreover, both the damaged cartilage from the WT-DMM mice and the OPG−/−-DMM mice were alleviated but only the deterioration of SCB in WT-DMM mice was alleviated after the administration of PTH (1–34). In vitro study, PTH (1–34) could promote the viability of chondrocytes, enhance the synthesis of extracellular matrix (ECM) (AGC, COLII, and SOX9) at the mRNA and protein level, but inhibit the secretion of inflammatory cytokines (TNF-α and IL-6).

Conclusion

Both wear of the cartilage was alleviated and aberrant remodeling of the SCB was inhibited in the WT mice, but only the cartilage-protective effect was observed in the OPG−/− mice. PTH (1–34) exhibited chondro-protective effect by decelerating cartilage degeneration in vivo as well as by promoting the proliferation and enhancing ECM synthesis of chondrocytes in vitro. The current investigation implied that the rescue of the disturbed SCB is dependent on the regulation of OPG while the chondro-protective effect is independent of modulation of OPG, which provides proof for the treatment of KOA.

The translational potential of this article

Systemic administration of PTH (1-34) could exert a therapeutic effect on both cartilage and SCB in different mechanisms to alleviate KOA progression, which might be a novel therapy for KOA.

Keywords

Teriparatide (PTH (1–34))

Knee osteoarthritis

Cartilage

Subchondral bone

Osteoprotegerin (OPG)

AbbreviationsOPG−/−

osteoprotegerin-knockout

DMM

destabilization of medical meniscus

ARRIVE

Animal Research: Reporting of In Vivo Experiments

PCR

polymerase chain reaction

S.I

subcutaneous injection

HPLC

High Performance Liquid Chromatography

Micro-CT

microcomputer tomography

Tb.Th

trabecular thickness

BV/TV

bone volume fraction

EDTA

ethylene diamine tetra acetic acid

SOFG

Safranin O-fast green

OARSI

Osteoarthritis Research Society International

PBS

phosphate buffer solution

DMEM

Dulbecco's Modified Eagle's Medium

EdU

5-ethynyl-2′-deoxyuridine

CLSM

confocal laser scanning microscope

GAPDH

glyceraldehyde-3-phosphate dehydrogenase

TNF-α

tumor necrosis factor-α

ELISA

enzyme-linked immunosorbent assay

RT-qPCR

quantitative reverse transcription polymerase chain reaction

NCBI

National Center for Biotechnology Information

SOX9

SRY-Box Transcription Factor 9

MMP13

Matrix Metallopeptidase 13

ADAMTS5

ADAM Metallopeptidase with Thrombospondin Type 1 Motif 5

ANOVA

one-way analysis of variance

© 2022 Peking University Shenzhen Hospital. Published by Elsevier B.V. on behalf of Chinese Speaking Orthopaedic Society.

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