Aging and Bone Health
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Join Dr. Joy Wu as she discusses the potential therapeutic approaches to age-related bone loss. Osteoporosis is one of the most common degenerative diseases of aging. Half of adult women and one-quarter of adult men can expect to sustain an osteoporosis-related fracture. While current approaches to the treatment of osteoporosis can lower the risk of fracture, there is still no cure. In this webinar, Dr. Wu reviews the pathophysiology of bone loss with aging, in particular the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts. She discusses stem cell sources of osteoblasts, anabolic signaling pathways, and targeting inflammation and senescence. Key Topics Include: - Describe how bone formation and resorption are coupled and regulate bone mass - Describe factors that contribute to aging-related bone loss - Discuss benefits and limitations of current osteoporosis therapies
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Aging and Bone Health
- 1. Aging and Bone Health Joy Wu, MD, PhD Associate Professor of Medicine Vice Chair, Basic and Translational Science Department of Medicine Copyright 2021 J. Wu, APS, and InsideScientific. All Rights Reserved. @JoyYWu
- 2. Mechanical support Protection Mineral storage Functions of the skeleton Hematopoiesis Endocrine FGF23
- 3. Osteoporosis has a high clinical and economic burden ▪ 50% of women and 25% of men over 50 will have an osteoporotic fracture ▪ Approximately 300,000 adults suffer hip fractures each year in the U.S. ▪ The one-year mortality following hip fracture exceeds 20% ▪ Costs associated with osteoporosis-related fractures are greater than $20 billion annually www.nof.org
- 4. Osteoporosis in Perspective ▪ Lifetime risk at age 50 50% 12% 0% 10% 20% 30% 40% 50% 60% Fracture Breast Cancer Women 20% 17% 0% 5% 10% 15% 20% 25% 30% Fracture Prostate Cancer Men
- 5. Bone mineral density across the lifespan Hendrickx, Nat Rev Rheum 2015
- 6. Prevalence of osteopenia and osteoporosis increase with age Wright, JBMR 2014
- 7. Dual energy X-ray absorptiometry (DXA) scan ▪ Measured at spine and hip (femoral neck and total hip) ▪ T score – compares patient’s BMD to reference young adult population – WHO classification: ▪ T > -1.0 = normal ▪ -2.5 > T > -1.0 = osteopenia ▪ T < -2.5 = osteoporosis ▪ Z score – compares patient’s BMD to age-matched population – Z < -2.0 => look for secondary causes Raisz, NEJM 2005
- 8. Fracture risk depends on BMD and age 0 2 4 6 8 10 12 14 16 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 10 year hip fracture risk (%) BMD T score “Osteoporosis” by bone density 80 Age 75 70 65 60 55 Recommended treatment threshold Weight: 150 lb Height: 66 in
- 9. Fragility fractures in osteoporosis Distribution of Fractures International Osteoporosis Foundation World Osteoporosis Day 2012 report
- 10. Bone physiology Seeman, NEJM 2006
- 11. Bone formation and bone resorption are coupled Nordstrand, Clin Exp Mets 2009
- 12. Aging and bone loss ▪ Hormonal – Declining estrogen levels ▪ Decreased osteogenic potential of mesenchymal stem cells ▪ Inflammation ▪ Cellular senescence ▪ Sarcopenia – Muscle-bone crosstalk
- 13. Cellular senescence increases with age Ito, Trends Cell Biol 2017 6 months 24 months Farr, JBMR 2016
- 14. Clearance of senescent cells prevents age-related bone loss Farr, Nat Med 2017
- 15. Senolytic treatment prevents age-related bone loss Farr, Nat Med 2017 D+Q = dasatinib (tyrosine kinase inhibitor) + quercetin (flavanol)
- 16. Approaches to treating osteoporosis Treatment options Block bone breakdown: Selective estrogen receptor modulators Bisphosphonates Denosumab Promote bone formation: Teriparatide Abaloparatide Romosuzumab
- 17. Sutkeviciute, Trends Endo Metab 2019 Teriparatide [PTH(1-34)] SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF-(NH2) PTHrP(1-34) AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTA-(NH2) Abaloparatide AVSEHQLLHDKGKSIQDLRRRELLEKLLXKLHTA-(NH2) Parathyroid hormone receptor agonists as anabolic therapies for osteoporosis
- 18. Teriparatide (PTH[1-34]) is an anabolic treatment for osteoporosis -2 0 2 4 6 8 10 12 14 16 Lumbar spine Femoral neck % change BMD PBO PTH 20 ug PTH 40 ug Neer, NEJM 2001
- 19. Complexities of PTH1R signaling ▪ Effects of intermittent vs continuous PTH on bone mass ▪ Waning of the anabolic effect ▪ Differential effects of combination therapy with anti-resorptives ▪ Differential effects of PTH vs PTHrP ligands ▪ Crosstalk with Wnt signaling ▪ Limitations – Boxed warning for risk of osteosarcoma (abaloparatide) – Requirement for daily self-injections
- 20. PTH effects on bone mass depend on administration kinetics Continuous PTH Intermittent PTH (once daily) Osteoblast activity Osteoblast activity Osteoclast activity Osteoclast activity Bone resorption Bone formation Net decrease in bone mass Net increase in bone mass
- 21. The anabolic effect of PTH is transient Finkelstein, JCEM 2009 Black, NEJM 2005
- 22. Combination with denosumab but not bisphosphonate is better than PTH alone ALN PTH PTH+ALN Teriparatide + bisphosphonate (oral alendronate) Finkelstein, JCEM 2010 Tsai, Lancet 2013 Teriparatide + denosumab
- 23. Miller, JAMA 2016 Abaloparatide is a PTHrP analogue
- 24. Ferrandon, Nat Chem Bio 2009 PTH but not PTHrP continues to signal after endocytosis
- 25. Mouse models to study PTH1R signaling X X Mice lacking Gsα in osteoprogenitors: GsαOsxKO mice Mice lacking PTH1R in osteoprogenitors: PTH1ROsxKO mice
- 26. Mice lacking Gsα in osteoprogenitors have severe osteoporosis ▪ Fractures of long bones and ribs at birth ▪ Dramatic loss of trabecular and cortical bone ▪ Failure of bone formation WT KO Wu, JCI 2011
- 27. Panaroni, JBMR 2015 Mice lacking PTH1R in osteoprogenitors have severe osteoporosis WT KO
- 28. Gsα promotes osteoblast commitment but restrains differentiation BMSCs * * WT KO Wu, JCI 2011 WT KO -gal Cre * * WT KO
- 29. 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 VOX-BV/TV BV/TV (%) WT PBS WT PTH KO PBS KO PTH PBS PTH WT KO PBS PTH WT KO * NS 12 weeks: Anabolic PTH does not increase bone mass in mice lacking Gsα in osteoprogenitors Sinha, JBC 2016
- 30. Surprising effect of PTH on Gsα-deficient osteoblasts Sinha, JBC 2016 WT/PBS WT/PTH KO/PBS KO/PTH WT KO PBS PTH
- 32. Sclerostin is an inhibitor of canonical Wnt signaling ▪ Product of SOST, mutated in sclerostosis (Brundow, 2001; Balemans, 2001) ▪ Can bind to LRP5/6 and inhibit canonical Wnt signaling (Semenov, 2005; Li, 2005) Baron, Nat Med 2013 Hamersma, Clin Genet 2003
- 33. Approaches to treating osteoporosis Treatment options Block bone breakdown: Selective estrogen receptor modulators Bisphosphonates Denosumab Promote bone formation: Teriparatide Abaloparatide Romosuzumab
- 34. GsαOsxKO mice have increased marrow adipocytes and reduced Wnt signaling Sinha, JBMR 2014 * * WT KO
- 35. Working model for Gsα and Wnt signaling in determining osteoblast vs adipocyte fate
- 36. Runx2 Runx2 β-cat β-cat TCF/LEF PTH PKA Gs Osteoblast gene program Proposed crosstalk between PTH and Wnt signaling
- 37. If we had unlimited osteoblasts, we could… ▪ Study disease mechanisms in vitro ▪ Perform high-throughput screening for novel therapeutic compounds ▪ Develop cell-based regenerative therapies – Fracture non-union – Osteonecrosis – Traumatic orthopaedic injuries – Tumor-mediated bone destruction
- 38. Stem cell-based sources of osteoblasts ▪ Bone marrow mesenchymal stem cells ▪ Embryonic stem cells ▪ Induced pluripotent stem cells ▪ Direct reprogramming
- 39. Stem cell-based sources of osteoblasts ▪ Bone marrow mesenchymal stem cells ▪ Embryonic stem cells ▪ Induced pluripotent stem cells ▪ Direct reprogramming
- 40. Skeletal organ complementation assay Runx2+/- ♂ Runx2+/- ♀ X E3.5 blastocyst Runx2 WT HET KO All ES/iPS Chimeric Chubb, Stem Cells 2017 Otto, Cell 1997 Runx2+/+ Runx2-/- ES/iPS cells
- 41. Skeletal contribution of ES cells WT KO ES injected KO E18.5 Chubb, Stem Cells 2017
- 42. Osx-Cre/+ DTA/+ X E3.5 GFP+ blastocysts PS cells Osx-Cre/+; DTA/+ DTA/+ 3.6% 5.8% 20% 16% 37.5% 51.6% 54.2% 55% Pluripotent stem cells can rescue skeletogenesis DTA/+ OsxCre/+;DTA/+ control Chubb, Stem Cells 2017
- 43. Pluripotent stem cells can rescue the bone marrow hematopoietic niche Control Runx2 -/- GFP DAPI 55.1% 65.1% 1.5% 21.2% ESCs iPSCs Chubb, Stem Cells 2017
- 44. But pluripotent stem cells can form teratomas in vivo Zhu, Biomaterials 2018
- 45. Can we differentiate pluripotent stem cells into mature osteoblasts in vitro? Fibroblast iPS cells OSKM GFP+ osteoblast? ES cells Osx-GFP Col1a1-GFP OC-GFP
- 46. Differentiation of Col1a1-GFP ES cells into osteoblasts Zhu, Biomaterials 2019
- 47. Direct reprogramming of fibroblasts into induced osteoblasts ▪ iOBs should: – Express Col1a1-GFP – Express osteoblast genes – Form GFP+ mineralized nodules in culture – Have a transcriptome that resembles osteoblasts – Have an epigenome that resembles osteoblasts – Form bone in vivo Takahashi, Nat Rev MCB 2016 Induced osteoblasts (iOBs)
- 48. iOBs express Col1a1-GFP and osteoblast gene markers Zhu, JBMR 2020
- 49. iOBs form GFP+ mineralized nodules Alizarin Red: Von Kossa: Zhu, JBMR 2020
- 50. iOB transcriptomes resemble osteoblast transcriptomes Zhu, JBMR 2020
- 51. iOBs contribute to bone formation in vivo iOB FB Zhu, JBMR 2020
- 52. Summary ▪ Osteoporosis is a disease of skeletal fragility ▪ The risk of fragility fractures rises sharply with age ▪ A cure for osteoporosis will require safe and sustained bone formation ▪ Current anabolic therapies target PTH1R and Wnt signaling pathways ▪ Stem cell-based sources of osteoblasts hold promise for skeletal regenerative medicine
- 53. Acknowledgments Cristina Panaroni Srilatha Swami Joshua Joshson Lance Bettinson Takaharu Kimura Hui Zhu Rodrigo Valderrábano Frederic Shapiro Dahee Chung Aria Nisco
- 55. Joy Wu, MD, PhD Associate Professor of Medicine Vice Chair, Basic and Translational Science Department of Medicine Copyright 2021 J. Wu, APS, and InsideScientific. All Rights Reserved. Thank you for participating! CLICK HERE to learn more and watch the webinar