Year in Review

1. Year in Review
Osteoarthrits Biology
Esmeralda Blaney Davidson
Experimental Rheumatology, Radboud UMC Nijmegen, the Netherlands
Acknowledgements:
Arjan van Caam and Peter van der Kraan

2. Personal selection of this year
Based on Osteoarthritis Biology
(cartilage, bone, inflammation)
Published between OARSI 2015 – OARSI 2016

3. Disruption circadian rhythm leads to OA
circadian
clock
Disruption of circadian rhythms induces
pathological changes specifically in murine
knee joints.
Mice harboring mutations in the core
circadian clock genes Clock and Casein
kinase 1ϵ (tau) fail to develop joint
pathology.
Runs via stimulation
of catabolic factors
Environmental disruption of circadian rhythm predisposes mice to osteoarthritis-like changes in knee joint.
Kc R, et al. J Cell Physiol. 2015 Sep;230(9):2174-83. doi: 10.1002/jcp.24946.

4. circadian
clock
IL1 and LPS disrupts chondrocyte clock
(reversible with dexamethasone),
whereas TNFalpha does not
IL1
TNF
Catabolic cytokines disrupt the circadian clock and the expression ofclock-controlled genes in cartilage via an
NFкB-dependent pathway.
Guo B, et al. Osteoarthritis Cartilage. 2015 Nov;23(11):1981-8. doi:10.1016/j.joca.2015.02.020.
IL-1 also disrupts BMAL in a
NFkB dependent manner
IL1 disrupts circadian rhythm

5. circadian
clock
The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.
Dudek M et al. J Clin Invest. 2016 Jan 4;126(1):365-76. doi: 10.1172/JCI82755. Epub 2015 Dec 14.
Reduction of BMAL1 expression in
articular cartilage from human knees
with OA
Cartilage-specific BMAL1 KO results in
progressive cartilage degradation
Loss of circadian rhythm induces OA

6. TGFβ
ALK1 ALK5
Smad1/5/8 Smad2/3
MMP13
circadian
clock
Loss of BMAL1 shifts TGF-β signaling
The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.
Dudek M et al. J Clin Invest. 2016 Jan 4;126(1):365-76. doi: 10.1172/JCI82755. Epub 2015 Dec 14.
*Blaney Davidson EN et al.
J Immunol. 2009
*

7. TGFβ
ALK1
Smad1/5/8
ALK5
Smad2/3
MMP13
circadian
clock
Loss of BMAL1 shifts TGF-β signaling
ALK1
Smad1/5/8
BMAL1
The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.
Dudek M et al. J Clin Invest. 2016 Jan 4;126(1):365-76. doi: 10.1172/JCI82755. Epub 2015 Dec 14.

8. TGFβ
ALK1 ALK5
Smad1/5/8 Smad2/3
MMP13
Top predicted upstream regulator
shared by OA subchondral bone
and OA articular cartilage
Jeffries et al A&R 2015 Dec
Vitamin D protects from OA in
OVX rats via TGFβ
Li et al O&C 2016 Feb
Halifuginone improves ACLT OA
Cui et al Ann Rheum Dis 2015 Oct
miR-193b inhibits TGFβ/Smad3
signaling and chondrogenesis
Hou et al FEBS Lett 2015 Apr
Smad3 KO leads to OA
Mori et al Am J Pathol 2015 Oct
Shift from Smad 2/3 to Smad1/5/8
in cartilage degradation and SBC
formation in spontaneous OA
Zhao et al J Orthop Res 2015 Oct
Neutralizing antibody against TGFβ
protects from cartilage damage and
SCB changes in ACLT rats
Xie et al Ann NY Acad Sci 2016 Feb
Smurf2 (Ub degradation of Smad1,
2, 3, and TGF-receptors)
Smurf 2 KO has milder
spontaneous and DMM-OA
Huang et al PLOS One 2016 Jan
miR-16-5p up in OA, upregulates
Smad3 and results in OA-like
changes in chondrocytes
Li et al Curr Pharm Des 2015
*

9. TGF-β influences autophagy
and vice versa
circadian
clock Ageing / OA

10. Autophagy
Autophagy control proteins Atg5 and LC3 are
reduced with age in cartilage in mice
The relationship of autophagy defects to cartilage damage during joint aging in a mouse model.
Caramés B et al. Arthritis Rheumatol. 2015 Jun;67(6):1568-76. doi: 10.1002/art.39073.

11. Autophagy
and aggravated age-related OA,
but not mechanically induced OA (MMT model)
KO of autophagy-gene Atg5
increased cell death
Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis.
Bouderlique T et al, Ann Rheum Dis. 2016 Mar;75(3):627-31. doi: 10.1136/annrheumdis-2015-207742. Epub 2015 Oct 5.

12. Autophagy
mTOR = repressor of autophagy
Upregulated in OA
cKO mTOR (cartilage) reduced OA
Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis.
Zhang Y et al. Ann Rheum Dis. 2015 Jul;74(7):1432-40. doi: 10.1136/annrheumdis-2013-204599. Epub 2014 Mar 20.

13. SIRT6 blockage increases senescense
Depletion of SIRT6 causes cellular senescence, DNA damage, and telomeredysfunction in human chondrocytes.
Nagai K et al. Osteoarthritis Cartilage. 2015 Aug;23(8):1412-20. doi:10.1016/j.joca.2015.03.024. Epub 2015 Mar 26.
Blocking SIRT6 increases MMP1 and -13
Blocking SIRT6 increases
premature senescence

14. SIRT6 reduces OA
Overexpression of Sirtuin 6 suppresses cellular senescence and NF-κB mediated inflammatory
responses in osteoarthritis development.
Wu Y et al, Sci Rep.2015 Dec 7;5:17602. doi: 10.1038/srep17602.
SIRT6 decreased
in OA
SIRT6 reduces OA
SIRT6 attenuated NFkB mediated responses

15. SIRT6 haploinsufficiency: more OA
Pivotal role of Sirt6 in the crosstalk among ageing, metabolic syndrome and osteoarthritis.
Ailixiding M et al, Biochem Biophys Res Commun.2015 Oct 23;466(3):319-26. doi: 10.1016/j.bbrc.2015.09.019. Epub 2015 Sep 8.
Sirt6 haploinsufficiency in mice: more OA
These data, including other data was concluded to suggest that Sirt6 +/- mice
fed an HFD were more susceptible to metabolic syndrome than WT mice.

16. Excersize/loading
Young Investigator Award TGFβ
ALK5
Smad2/3

17. Exercise intervention increases expression of bone morphogenetic proteins and prevents the progression of
cartilage-subchondral bone lesions in a post-traumatic rat knee model.
Iijima H et al. Osteoarthritis Cartilage. 2016 Jan 19. pii: S1063-4584(16)00025-X. doi: 10.1016/j.joca.2016.01.006.[Epub ahead of print]
Treadmill walking prevented cartilage and subchondral bone lesions in DMM in rat
and increased BMP2 and -6.
Excersize protects

18. Epiphyseal trabecular bone (BV/TV) and trabecular thickness
increased in loaded and contralateral (non-loaded) knees.
Non-load changes due to subsequent alterations in gait.
Intermittent applied mechanical loading induces subchondral bone thickening that may be intensified locally
by contiguous articular cartilage lesions. Poulet B et al. Osteoarthritis Cartilage. 2015 Jun;23(6):940-8.
Contralateral effects of
joint loading

19. Matrix cross-linking-mediated mechanotransduction promotes posttraumatic osteoarthritis.
Kim JH et al.Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):9424-9. doi: 10.1073/pnas.1505700112. Epub 2015 Jul 13.
OA  more cross-linking enzymes
Enhanced stiffness 
enhanced degradation enzymes
Blocking cross-linking enzymes reduces OA
Matrix stiffness matters

20. Exercise induces lubricin
Physical activity ameliorates cartilage degeneration in a rat model of aging: a study on lubricin expression.
Musumeci G et al. Scand J Med Sci Sports. 2015 Apr;25(2):e222-30. doi: 10.1111/sms.12290. Epub 2014Jul 9.
Young rats
Physicalactivity
Adult rats
sedentary
Old rats
young adult old
physical activity

21. Lubricin protects from OA
Treatment with recombinant lubricin attenuates osteoarthritis by positive feedback loop
between articular cartilage and subchondral bone in ovariectomized rats. Cui Z et al. Bone. 2015 May;74:37-47.
early
late

22. Lubricin inhibits TLR2/4 activity
TLR2 TLR4
The interaction of lubricin/proteoglycan 4 (PRG4) with toll-like receptors 2 and 4: an anti-inflammatory role
of PRG4 in synovial fluid. Alquraini A et al. Arthritis Res Ther. 2015 Dec 4;17:353. doi: 10.1186/s13075-015-0877-x.

23. Pain in OA lower by lubricin
Lubricin binds TLRs and reduces pain in OA
Lubricin can bind to and regulate the
activity of TLRs 2,4,5, leading to
downstream changes in inflammatory
signalling independent of HANFkB dependent
Lubricin/Proteoglycan 4 binds to and regulates the activity of Toll-Like Receptors In Vitro.
Iqbal SM et al. Sci Rep. 2016 Jan 11;6:18910. doi: 10.1038/srep18910.

24. Pain through TLR
Damage-associated molecular patterns generated in osteoarthritis directly excite
murine nociceptive neurons through Toll-like receptor 4.
Miller RE et al Arthritis Rheumatol. 2015 Nov;67(11):2933-43. doi: 10.1002/art.39291
Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human
Intervertebral Discs. Krock E et al. J Biol Chem. 2016 Feb 12;291(7):3541-51.
doi: 10.1074/jbc.M115.675900. Epub 2015 Dec 14.
Blocking TLR4 prevented S100A8-
induced DRG response, but TLR4-/-
not protected from mechanical
allodynia – multiple pathways
involved, like TLR2?
TLR2 agonist induces NGF

25. PKCδ-/- have less OA, but more pain
Associated with elevated TrkA and NGF
PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint
pathology by augmenting NGF/TrkA-induced axonal outgrowth.
Kc R et al. Ann Rheum Dis. 2016 Jan 18. pii: annrheumdis-2015-208444. doi: 10.1136/annrheumdis-2015-208444.

26. NGF in cartilage, upregulated by injury
FGF2, TAK1 and Src kinase dependent
snap frozen
vehicle 4hrs
inhibitor
FGFRi TAK1i SRCi MEKi p38i
Nociceptive sensitizers are regulated in damaged joint tissues, including the articular cartilage,
when osteoarthritic mice display pain behaviour.
Driscoll C et al. Arthritis Rheumatol. 2015 Nov 25. doi: 10.1002/art.39523.

27. TrkA or NGF blockage inhibits pain
behaviour in rats and dogs
Blocking the tropomyosin receptor kinase A (TrkA)
receptor inhibits pain behaviour in two rat models
of osteoarthritis.
Nwosu LN et al Ann Rheum Dis. 2015 Aug 18. pii:
annrheumdis-2014-207203. doi:
10.1136/annrheumdis-2014-207203.
A canine-specific anti-nerve growth factor
antibody alleviates pain and improves mobility
and function in dogs with degenerative joint
disease-associated pain.
Lascelles BD et al.BMC Vet Res. 2015 Apr
30;11:101. doi: 10.1186/s12917-015-0413-x.
anti-NGF
Long-term analgesic effect of a single dose of anti-
NGF antibody on pain during motion without
notable suppression of joint edema and lesion in a
rat model of osteoarthritis.
Ishikawa G et al. Osteoarthritis Cartilage..2015
Jun;23(6):925-32. doi: 10.1016/j.joca.2015.02.002.
Epub 2015 Feb 9.
Anti-TrkA in MIA and MNX
Anti-NGF in dog DJD and rat MIA
activity
Weightbearingassymetry
gait

28. circadian
clock Ageing / OA
Scheme of this year in review
Toll-like Receptor Signaling: The effects of
circadian rhythms on Toll-like receptor
responses in murine macrophages
Sidhu et al J Immunol 2015 194:194.14

29. circadian
clock Ageing / OA
Scheme of this year in review