DISCLOSURES TOPICS" PATHOPHYSIOLOGY of OSTEOPOROSIS: Pathways That Control Bone Remodeling! Why Do Bones Remodel?" Nothing to disclose

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1 PATHOPHYSIOLOGY of OSTEOPOROSIS: Pathways That Control Bone Remodeling Dolores Shoback, MD Professor of Medicine, UCSF Staff Physician SF/VAMC May 19, 2017 DISCLOSURES Nothing to disclose No conflicts of interest TOPICS Bone remodeling and modeling Imbalances underlie bone loss, repair Resorption RANK-L/RANK/OPG Formation - Wnt/LRP5/Beta catenin Pathogenesis of bone loss (menopause, age) Immune mediators, microbiome estrogen deficiency Coupling hypothesis - resorptive function and signaling pathways of osteoclasts regulate osteoblast function BONE REMODELING process of coupled resorption and formation that maintains bone mass in adult life (10%, slow) BONE MODELING process that shapes bones as we grow & develop (childhood, adolescence); also occurs at low rate throughout life; resorption and formation are uncoupled and they occur on different surfaces (basis for anabolic therapies) Baron and Hesse, JCEM, 2012 Why Do Bones Remodel? Microfracture Is Repaired through Targeted Remodeling Allows skeleton to -- Respond to mechanical loading (modeling) Repair microdamage ( wear and tear ) & prevent accumulation Maintains quality control Segovia-Silvestre T et al, Hum Genet, 2009

2 Why Do Bones Remodel? Allows skeleton to -- Respond to mechanical loading (modeling) Repair microdamage ( wear and tear ) & prevent accumulation Maintains quality control Release minerals (Ca and phosphate) & growth factors stored in matrix into circulation Important in skeletal homeostasis (role in remodeling imbalance of age) RANK-Ligand/ RANK/ Osteoprotegrin Pathway ogenesis: Hormones, Growth Factors, Cytokines Stimulate Expression of RANK-L {RANK+RANK-L Interact} Glucocorticoids Vitamin D PTH CFU-M RANKL Pre-fusion PGE2 Osteoprotegerin (OPG) Prevents RANK-L/ RANK Interaction & Inhibits OC Activity [OPG=Circulating Inhibitor ] CFU-M RANK Pre-fusion +mcsf Multinucleated IL-1 PTHrP TNF-α Activated OPG Multinucleated Hormones Growth Factors Cytokines Denosumab does the same thing Activated Osteoblasts Bone Formation Osteoblasts & BM Stromal Cells Boyle WJ et al. Nature 2003;423:337; Hofbauer LC, Schoppet. M. JAMA 2004;292:490 RANK IL-11 IL-6 RANKL Bone Resorption Boyle WJ et al. Nature 2003;423:337 Bone Resorption OSTEOBLAST LINEAGE CELLS Bone Formation LRP5/Wnt/β-Catenin Mesenchymal stem cells, pre-ob s, mature OB s, bonelining cells, stromal cells, and osteocytes Produce matrix and mineralize it Mechanical support Matrix - reservoir of Ca, phosphate, growth factors, hormones Secrete endocrine & paracrine factors FGF23, DMP1, etc Modulate development of tri-lineages of blood cells Play role in metabolism, male reproduction Function and numbers of cells in OB lineage decline with aging many factors responsible *

3 Canonical Wnt Signaling NEW bone formation (quiescent & remodeling surfaces) Lewiecki et al, Nat Rev Rheumatol, 2011 Sclerostin Secreted by Osteocytes Negatively Regulates Bone Formation Wnt Inhibition WIF1 (Wnt inhibitory factor) or SFRP (secreted frizzled related protein) sequester Wnt ligand then, Axin & APC associate with GSK-3 β increase phosphorylation of β-catenin β-catenin~p à ubiquinated à proteasome for degradation NO bone made Other inhibitors: Ncadherin inhibits LRP5/ Wnt; sclerostin & DKK1 If no Wnt present, no signaling - βcatenin levels are LOW Wnt signaling (OB, OB precursors) à recruits IC protein Axin which moves to tail of LRP5/6 (because of interaction with Dvl) Complex forms, recruits FRAT1 and glycogen synthase kinase-3 β Complex forms & inhibits βcatenin phosphorylation Non-phosphorylated β-catenin accumulates in cytosol, goes to nucleus β-catenin binds to LEF/TCF FINAL elements and activates OB + OPG à transcription program à (osteoprotegerin) RSPO & norrin modulate Wnt Baron R, Kneissel M, Nat Med 2013 Sclerostin* Mature Osteoblasts New bone Osteocyte à Baron R, Kneissel M, Nat Med 2013 Ott SM. JCEM 2005; Semenov M, et al. JBC 2005; Semenov MV, et al. JBC 2006; Li, et al. JBC 2005 A Sclerostin Inhibits Wnt Pathway * Pre-osteoblast lining cells Mesenchymal stem cells Bone Loss of function mutations à HIGH bone mass Targeting therapy to neutralizing Scl (Mab) Loss of Function Sclerostin Mutations Both SOST/sclerostin genes mutated Child (A), adult (B,D) with SCLEROSTEOSIS Carrier with one mutant allele (1/2 dose) B Adult (C) healthy with dense bone, elevated BMD T- and Zscores (spine, hip) no fractures or deformities (over lifetime) D New Bone Formation * Neutralizing MAb to sclerostin Gennari L et al, Exp Opin Pharmacother, 2014 C Gardner JC et al, JCEM, 2005

4 hpth hpthrp ABL 1 1 Abaloparatide Novel analog of hpthrp (1-34) Comparison of Sequence Identity % hpthrp 38% hpthrp Abaloparatide design: Potent bone anabolic activity with limited/no effects on resorption; identify analogue that favored binding to R G form of PTHreceptor ( biased agonist ) Different ligands favor different PTH-R1 conformations (R 0 for PTH, R G for PTHrP) * *Anabolic effects favored with strong peak responses but shorter overall camp signals *Preclinical studies supported Cheloha, RW et al. (2015) Nat. Rev Endo. Pathophysiology of Bone Loss Menopause Remodeling increases, more BMU s are formed, deeper resorption pits (b) Amount of bone formed - less than what was resorbed Remodeling imbalance occurs (negative) - uncoupling With time - structural deterioration of bone Thinned trabeculi, decreased connectivity, perforations Lewiecki EM, Nat Rev Rheumatol, 2011 Effects of Estrogen on Bone Resorption E Stromal cells/pre-obs IL1 TNF Monocytes +E IL6 mcsf IL11 GM-CSF RANKL OPG TGFb +E Early OC progenitors M-CSF IL-6 IL-1 TNF RANKL Active osteoclasts - E +E RANK +E -E resorption resorption Estrogen: dampens IL-1, TNFα à decreases IL6, IL11, GM-CSF, RANKL, mcsf; increases OPG, Estrogen deficiency: increases TNFα, IL1 à releases IL6, M-CSF, IL11, GM-CSF, RANKL à stimulates OC s; decreases OPG, Gut Microbiome (Steves et al, JBMR, 2015) Billions of bacteria live in symbiosis with our bodies influence health and disease Gut MB à host metabolic potential & innate & adaptive immune systems Aging à à à Inflammation à à à Disease Microbiome Role in osteoporosis, OA, gout, RA, sarcopenia, frailty MODIFIABLE - - by probiotics (bacteria in food or dietary supplements) and prebiotics (usu complex CHO fibers in fruits/vegetables)

5 Gut MB May Play a Fundamental Role in Bone Mass Regulation (Igbal et al, JCI, 2016) Gut Microbiome (Hernandez CJ et al, JBMR, 2016) Benefits to the host Vitamin production (many) Extracts nutrients and energy from diet Metabolic function (metabolites à host) Regulates immune system Protects against pathogens getting in How might the microbiome help bone? Enhance absorption of minerals (probiotics, prebiotics) Enhance barrier function Enhance immune system (good or bad) A LOT OF EVIDENCE FOR MB INVOLVEMENT FOR BONE IN HUMANS - MOST IS INDIRECT Normal gut flora antigens (in MB) are presented to APC, T cells Pro-inflammatory cytokines made (ESTROGEN will normally dampen this, maintain barrier via gap junctions) Probiotics: Signal through APCs/T cells to reduce TNF-α, IL1-β, RANKL; increase IL10 and OPG and Treg activity Increase May be estrogen-like molecules à restore nl estrogen signaling and barrier function NO estrogen, these cytokines drive resorption systemically; barrier function also reduced (gap junctions faulty) Sex Steroid Deficiency (SSD) Associated Bone Loss Is Microbiota-Dependent and Prevented by Probiotics (Li et al, J Clin Inv, 2016) Female mice (SSD) é bone mass Mechanisms for Age-related Bone Loss - Sex steroid def present (women, men) + nutritional issues (Ca & vitamin D def, often secondary HPT, sarcopenia) Intrinsic defects in marrow stromal cells with aging à impaired proliferation & differentiation ( senescent OB s ) é gut permeability, expanded TH17 cells (OC-genic pop. T cells) é OC-genic cytokines in small intestine, marrow (TNF, RANK-L, IL-17) Bone loss (micro-ct, histomorphometry, BTM s) These events don t happen to mice kept under germ-free conditions. Twice weekly treatment of SSD mice with probiotic Reduce/reverse trabecular bone boss (4 weeks after OV) No effects on cortical bone Cytokines, T cell profiles (gut, bone) are ones that less pro-resorptive More fat Probiotics improve trabecular BMD in control mice Several potential mechanisms postulated * Khosla S, J Ger Med Sci, 2013

6 Age-related Osteoporosis Imbalance in the bone formation response to ongoing bone resorption Bone as tissue ages Changes in material properties affect strength and in matrix components affect constituents/composition - released into microenvironment Is the problem only with osteoblasts? lineage involved? Factors Released from Bone with ic Resorption Sims NA, Ng KW, Curr Osteo Rep, 2014 IGF-1 Promote bone cell proliferation, differentiation and IGF-1 levels in bone fall with age Matrix changes with aging May underlie reduced bone formation responses seen with aging in men and women IGF-1 IGF-1 Coupling Factor Hypothesis (OCà OB) - -Derived Factors S1P/Rho GTPase Control of Osteoblast Lineage Cells PRE-OSTEOBLAST BMP6 Sphingosine-1 Phosphate Wnt10b S1P RhoA GTPase OSTEOBLAST SCLEROSTIN PRE- Pederson et al. PNAS 105:20764, 2008 Quint et al, JBC 2013; Migration Chemotaxis MSC/OSTEOBLAST Released From Bone Matrix During Resorption from OC Activity Influences Migration of OB Cells MSC Osteoblasts LIF Leukemia inhibitory factor CCL16 chemokine OSTEOBLAST Tang et al, Nat Med, 2009; Ota et al, Bone, 2013; Migration Sites of Resorption Fracture Repair

7 s Respond to Released From Matrix During Resorption Conditional Deletion of Receptor II in s (mice) (Weivoda et al, JBMR 31:76; 2016; provided by MJ Oursler) RI RII RI Amount with aging Bone mass reduced à trabecular osteopenia Bone weaker by mechanical testing OB numbers, serum P1NP, bone formation rates by histomorphometry (OB) - LOW Resembles senile bone loss s: Key Regulators of Bone Metabolism, SUMMARY Release Coupling Factors, Act Directly on OB s è Process May Be Altered with Aging OSTEOBLAST Pre- OSTEOBLAST CCL16 S1P Wnt 1 Wnts 1, 4,10b MSC Less with age Pre- OC s à OB function (via Wnt) Sex hormone deficiency and age-related bone loss Imbalances in remodeling, defects in coupling that favor net LOSS of bone mass Postmenopausal osteoporosis - Altered cytokine milieu (bone, intestine) Changes in T cell subpopulations (humans too) Gut microbiome may be key Aging-related bone loss - Defective OB function, senescent OB s Altered communication of OC s with OB s Changes in matrix composition (with aging) contribute