2. Disease of the joints
characterized by:
– Progressive articular
cartilage loss
– New subchondral bone
formation
– New bone and
cartilage formation at
joint margins
– Low level synovitis
Definition of OA
& PAIN!
6. Pathogenesis in OA
• Decreases in:
– GAG synthesis
– Size of Aggregates,
GAG & Hyaluronic acid
– Collagen x-linking
– Water content
• Chondrocyte apoptosis
• Traumatic damage
7. Osteoarthritis (OA)
Higher incidence of OA in elderly
⚫2020: 595 million people had OA, 7.6% of the
global population
⚫2050: increase 74.9% for knee, 48.6% for hand,
78.6% for hip, and 95.1% for other types of OA
Lancet Rheumatol 2023; 5: e508–22
11. OA in Taiwan
• > 65 y/o: 11.53%
• >70 y/o: 70% have knee OA
• Knee OA total medical cost: 3.06 billion
NT
• Patients with clinic visit due to knee OA:
528,000
http://www.moi.gov.tw/stat/news_content.aspx?sn=8057
http://www.doh.gov.tw/CHT2006/DM/DM_2.aspx? NOW fod
list_no=12029&class_no=440&level_no=3
http://www.doh.gov.tw/CHT2006/DM/DM_2.aspx? NOW fod
list_no=12025&class_no=440&level_no=3
12. Risk Factors for OA
Systemic Risk Factors
• Age
– 10-fold increase from 30→65
• Genetics (generalized)
• Gender
– Men <50: lower risk
– Women >50: higher risk
• Nutritional
– Low vitamin C and D intake
Joint Biomechanical Risk
Factors
• Joint trauma
• Obesity (knee, hip, hand)
• Occupation
• Abnormal joint
biomechanics
– Dysplasia, malalignment,
instability, abnormal
innervation
• Knee extensor wkness
• Sports w/ joint risk
13. Post-traumatic OA (PT-OA)
• Ligamentous or capsular Injury in joint:
increase >10-fold of OA risk
• Articular fracture:
increase > 20-fold of OA risk
• In USA: 6 million PT-OA p’ts
3 billion USD for treating PT-OA
Anderson et al, JOR 2011
15. • OA is a complex syndrome rather than a
single disease.
• OA subgroups can be characterized based
on differences in prognosis, therapeutic
response or disease mechanisms.
• OA phenotyping includes the identification
of key phenotypic characteristics,
appropriate statistical approaches and
extensive validation.
16.
17.
18. • OA is a painful chronic disease, and the
associated pain mechanisms are complex.
• Peripheral sensitization and central
sensitization contribute to OA pain.
• Nociceptive, inflammatory and
neuropathic pains are part of the OA pain
phenotype but are differentiated by
mechanisms.
19.
20. • Inflammatory pathways, cartilage and
subchondral bone are the three main targets for
the development of disease-modifying OA drugs.
• Some existing therapeutic agents, such as
bisphosphonates, strontium and hyaluronic acid,
may act as potential disease-modifying OA drugs.
• Non-pharmacological treatments are likely to
provide alternatives for disease modification in
OA.
24. • Anti-nerve growth factor therapy is a promising
therapeutic for OA pain, despite reported
adverse effects.
• Therapies for OA pain are rapidly transforming
beyond traditional painkillers toward more
mechanism-based interventions.
• Neurolysis is being investigated for OA pain,
but efficacy profiles and long-term effects
require further study
25. Neurotrophin, NGF
• Expression is markedly increased in human
pain states, including OA
• Profound sensitizing effects on the nociception
• Tanezumab (Pfizer and Eli Lilly), fasinumab
(Regeneron and Teva) and fulranumab
(Janssen and Amgen)
• Anti-NGF therapy: rapidly progressive OA and,
less commonly, with osteonecrosis,
• FDA hold on all clinical trials of NGF
antagonists in 2010. Restart 2015
39. Pathophysiology: synovitis
• The synovitis seen in OA has a predominance of
macrophages, while the synovitis of RA has a
predominance of T cells. This reflects activation of the
innate immune response in OA joints, likely due to
damage of joint tissues resulting in a chronic wound type
of environment.
• OA synovitis is more focal than in RA; in the knee, it is
commonly found in the suprapatellar pouch.
• Synovitis plays a prominent role in joint destruction in RA,
while its role in the progression of OA may be limited to a
subset of individuals.
47. Unique characteristics of Stem
Cells
• Stem cells can regenerate
– Unlimited self renewal through cell division
• Stem cells can specialize
– Under certain physiologic or experimental
conditions
– Stem cells then become cells with special
functions such as:
• Beating cells of the heart muscle
• Insulin-producing cells of the pancreas
48. Potential of Stem Cells
• Totipotent (total):
– Total potential to differentiate into any adult cell
type
– Total potential to form specialized tissue needed
for embryonic development
• Pluripotent (plural):
– Potential to form most or all 210 differentiated adult
cell types
• Multipotent (multiple):
– Limited potential
– Forms only multiple adult cell types
• Oligodendrocytes
• Neurons
50. Stem cells application
• Stem cells are undifferentiated cells that
have many potential scientific uses:
– Cell based therapies
• Often referred to as regenerative or reparative
medicine
– Therapeutic cloning
– Gene therapy
– Cancer research
– Basic research
51. Stem cells
• Embryonic stem cell (hESC) (pluripotent or
totipotent)
• Induced pluripotent stem cells (iPSCs)
(pluripotent)
• Mesenchymal stem cells (MSCs) (multipotent)
• In 2016, 351 US businesses engaged in
frequently unproven and direct-to-consumer
marketing of different stem cell interventions was
offered at 570 clinics
55. Safety issues regarding iPSC-
based therapy
Undifferentiated iPSCs are not safe
• As for hESCs the main safety issue regarding iPSC-
based therapy is the risk of teratoma formation which
can happened if patient receive iPSC-derived cells that
contain undifferentiated Ipsc
• Uncontrolled proliferation and differentiation of
transplanted undifferentiated iPSCs may result in
generation of tumors and/or undesired differentiation of
iPSCs in broad range of somatic cells
57. Safety issues regarding MSCs-
based therapy
• Despite these promising results, safety issues
regarding MSCs-based therapy are still a matter
of debate, especially in the long-term follow up
• The primary concern is unwanted differentiation
of the transplanted MSCs and their potential to
suppress anti-tumor immune response and
generate new blood vessels that may promote
tumor growth and metastasis.
58. MSC之再生醫學應用
6
9
Stem. Cell. Res. Ther. 2021; 16: 323-353.
Many clinical trials based on MSCs for the treatment of
a variety of diseases, demonstrating their capability in
the treatment of dermatological, musculoskeletal,
neurological, cardiovascular, respiratory, renal,
gastroenterological and urological conditions, etc.
59. MSC 治療骨關節炎 MSC-based suppression
of immune response in
osteoarthritis
- Suppress migration of macrophages and reduce their capacity to
produce
pro-inflammatory TNF-α
- Inhibit maturation of DCs and alter their secretion profile resulting in
decreased production of TNF-α
- Directly decrease production of Th1 and Th17 cytokines in effector T
cells
- Decrease activation and proliferation of autoreactive B lymphocytes
Pharmacother. 2019 ; 109: 2318-2326.
60. Schematic representation of the potential therapeutic
strategies utilizing mesenchymal cells (MSCs)
therapy for cartilage repair and regeneration.
Biomedicines. 2021; 9: 785.
62. Difficulties of Stem Cell Therapy
• Autologous without expansion: limited cell
number (>10 million cells)
• Stem cell products: (autologous or allogeneic)
GTP, CMC, high cost
• IPSCs: GTP, CMC, high cost,
risk of transformation
80. 療效評估方式
醫師專業評估
• 疼痛視覺類比量表(Visual Analog Scale for pain, VAS pain)
• 西安大略及麥可麥司特大學關節炎量表 (Western Ontario and
McMaster Universities Osteoarthritis Index, WOMAC)
• 膝關節炎疼痛指數評分表(Lequesne's index)
• IKDC(International Knee Documentation Committee)
• KOOS(Knee injury and Osteoarthritis Outcome Score)
• Tegner Lysholm Knee Scoring Scale
• 治療前後X-ray的影像評估
病人觀感&病人生活品質
生活品質量表 (The MOS 36-item short-form health survey,
SF36)
療效會依總分數做評估:
-有療效:
總分數比治療前之總分數高於(含)10%
-沒有療效:
總分數比治療前之總分數低於10%
81. Take home message
• OA treatment: according to
– Stage
– Patient condition
– Life quality demanding
• No medication for cure, only palliative
– Treatment goal and side effect
• Surgery for end stage OA if condition
suitable
• Stem cell therapy maybe helpful