Andrea Bonetto, PhD. Bone and Muscle Crosstalk: mechanical and biochemical interactions (2)

Transcription

1 Andrea Bonetto, PhD Bone and Muscle Crosstalk: mechanical and biochemical interactions (2) March 29, 218

2 Osteokines vs. Myokines Muscle wasting Osteokines Activin A TGF-β IGF-1 BMP-2 Myokines IL-6 IGF-1 Myostatin FGF-2 Bone loss

3 Activin A inhibition improves bone quality and strength in dystrophic mice Puolakkainen et al. 217, BMC Musculoskelet Disord

4 Inhibition of Activin A improves muscle and bone quality in mice affected with osteogenesis imperfecta

5 Aromatase inhibitors exacerbate bone loss w w w.im pact j ournals.com / oncot arget/ Oncotarget, 2 1 7, Vol. 8, ( No. 5 ), pp: Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates m uscle w eakness in vivo Laura E. W right 1, Ahm ed A. Harhash 1, W ende M. Kozlow 2, David L. W aning 3, Jenna N. Regan 1, Yun She 1, Sut ha K. John 1, Sreem ala Murthy 1, Maryla Niew olna 1, Andrew R. Marks 4, Khalid S. Moham m ad 1, Theresa A. Guise 1 1 Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA 2 Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA, USA 3 Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA 4 Department of Physiology, Columbia University, New York, NY, USA Correspondence to: Laura E. Wright, laewrig@iu.edu Keywords: b rea st c anc er, b one, meta stasis, aroma ta se inhib itor, skeleta l musc le Received: October 2, 216 Accepted: November 23, 216 Published: December 25, 216 ABSTRACT Research Paper Arom at ase inhibit ors ( AI s) cause m uscle w eakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI - induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underw ent ovariect om y ( OVX) or sham surgery and w ere treated w it h vehicle or AI ( letrozole; Let). An OVX-Let group was then further treated with bisphosphonate ( zoledronic acid; Zol). At week three, trabecular bone volume was measured and m ice w ere inoculated w ith MDA- MB cells into the cardiac ventricle and follow ed for progression of bone metastases. Five w eeks after tumor cell inoculation, tumorinduced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let- Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle- specific force of the extensor digitorum longus muscle w as reduced in OVX- Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. I n summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI -induced osteoclastic bone resorption using a bisphosphonate attenuated the developm ent of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically. INTRODUCTION Breast cancer is the most commonly diagnosed cancer in women [1] and the majority of breast tumors are hormone-responsive INDIANA [2]. Adjuvant UNIVERSITY endocrine therapies that impair the action of estrogen on breast tissue have become an important treatment strategy, reducing the risk (ER)-positive disease [3-5]. Aromatase inhibitors, which block the rate-limiting step of estrogen biosynthesis [6], have replaced selective estrogen receptor modulators (SERMs; e.g., tamoxifen) as the standard of care in postmenopausal breast cancer patients due to improved disease-free survival [7, 8]. AI treatment regimens in the adjuvant setting are typically administered for e fiv years Figure 3: Bone volume and microarchitecture were compromised in nude mice after three weeks of estrogen deprivation treatment. Three weeks after OVX/sham surgery and the commencement of drug treatments, mice were anesthetized r with isofluane and bone microarchitecture was assessed in the proximal tibia by micro-computed tomography (μct4; SCANCO Medical AG). Panel A. Trabecular bone volume (BV/TV), Panel B. connectivity density (1/mm 3 ), Panel C. trabecular number (1/mm), Panel D. trabecular separation (mm), Panel E. trabecular thickness (mm), and Panel F. structure model index are expressed as mean ±SEM and differences

6 Cancer-derived factors promote muscle wasting, i.e. cachexia

7 Cancer-derived factors promote loss of bone mass Loss id BMD and BMC directly correlates with tumor aggressiveness Bonetto et al. 217, Front Physiol

8 Cancer growth associates with bone decay Rate of bone decay correlates with tumor aggressiveness Bonetto et al. 217, Front Physiol

9 Loss of bone mass correlates with bone frailty Aggressive tumors associate with exacerbated bone frailty Bonetto et al. 217, Front Physiol

10 Aggressive tumors exacerbate the muscle and bone phenotypes Bonetto et al. 217, Front Physiol

11 Bone metastases promote high TGFβ and muscle weakness

12 Chemotherapy affects bone tissue Chemo- and radiotherapy have been reported to play a role in bone loss by: directly targeting bone mass promoting indirect systemic effects affecting bone remodeling causing myelosuppression

13 Tb.N (/mm) Tb.Pf (/mm) Conn. D (/mm 3 ) BV/TV (%) Tb.Th (mm) Tb.Sp (mm) Carboplatin promotes bone loss 25 Vertebra.1 Vertebra.4 Vertebra Ctrl Carboplatin. Ctrl Carboplatin. Ctrl Carboplatin 5 4 Vertebra 5 4 Vertebra 2 15 Vertebra Ctrl Carboplatin Ctrl Carboplatin Ctrl Carboplatin Bonetto Lab, unpublished

14 Force (g) Force (g) Force (g) BW increase Weight / 1mg IBW Carboplatin causes muscle wasting IBW d3 d5 d7 d9 BW Carboplatin (8mg/Kg) d11 d13 Days d15 d17 d19 d21 d GSN Muscles Tibialis Quadriceps Heart Carboplatin (8mg/Kg) Grip strength (day 7) Carboplatin Grip strength (day 14) Carboplatin Grip strength (day 21) Carboplatin Bonetto Lab, unpublished

15 determines loss of muscle mass and bone tissue Wk. 1 Wk. 2 Wk. 3 Wk. 4 Wk. 5

16 Fold change Grams (g) causes loss of body weight and muscle mass Week Week 1 BW increase Week 2 Week 3 Week BW change +

17 Variation vs. baseline Chemotherapy leads to muscle weakness 1.6 Fat tissue 1.4 Lean tissue Baseline Week 1 Week 2 Week 3 Week 4 Week Baseline Week 1 Week 2 Week 3 Week 4 Week 5 +

18 Weight / 1mg IBW Weight / 1mg IBW Weight / 1mg IBW Weight / 1mg IBW Weight / 1mg IBW Weight / 1mg IBW Weight / 1mg IBW administration affects muscle mass Tibialis anterior Gastrocnemius Quadriceps Heart Liver Spleen Fat +

19 CSA (mm 2 ) Force (g) Muscle size and strength are affected by chemotherapy Muscle fiber size Grip strength +

20 causes loss of trabecular bone, and counteracts such event +

21 % mm % Cortical bone is not affected by chemotherapy 15 Ct.BV/TV.15 Ct.Th 6 Porosity

22 Vertebral bone shows similar phenotypes in association with chemotherapy +

23 pg/ml pg/ml IL-6 and Activin A may be involved in promoting bone loss in association with chemotherapy IL Activin A +

24 Grams (g) BW change vs. IBW BW change vs. IBW Females are apparently more resistant to chemotherapy sex-related differences? Days Days 4 BW change Males Females Bonetto Lab, unpublished

25 Grams (g) Weight / 1mg IBW Weight / 1mg IBW Force (g) Female mice show milder wasting following chemotherapy administration Quadriceps -2% -1% Muscle force -17% -6% Fat (EchoMRI) -47% -17% Gonadal Adipose Tissue -63% -53% Males Females Bonetto Lab, unpublished

26 Tb. Sp (mm) Tb.N Tb. Sp (mm) Tb.N BV/TV (%) Tb. Th (mm) BV/TV (%) Tb. Th (mm) Chemotherapy-induced bone loss is exacerbated in male mice Femurs Vertebrae Bonetto Lab, unpublished

27 Bone and muscle tissue are lost following burn injury

28 Preservation of bone tissue positively affects muscle mass in burn patients

29 Fiber diameter (mm) Pamidronate does not preserve fiber size in myotubes exposed to cancer media Control C26 CM C26 CM + Pamidronate 15 C26CM + Pamidronate 1 5 Control C26 CM C26 CM + Pam Bonetto Lab, unpublished

30 Fiber diameter (mm) or chemotherapy Control + Pamidronate 15 1 C26CM + 5 Control + Pam Bonetto Lab, unpublished

31 um Bone-derived factors affect muscle fiber size in C2C12 myotube cultures Control Burn Burn + Pamidronate 2 5 M y o tu b e s iz e $ 5 C o n tr o l P B u r n e d P B u r n e d P + P a m id r o n a te Bonetto/Bonewald Labs, unpublished

32 Questions to Andrea Bonetto

33 Group Readiness Assessment Test (GRAT)

34 1- Cancer promotes? A. Bone loss, regardless of the cancer type B. Bone decay, but only in the advanced stages and in a tumor type-dependent manner C. Larger muscles and bones D. Stronger bones, but only the long ones

35 2- Animals affected with muscular dystrophy? A. Present muscle atrophy B. Are characterized by loss of bone mass C. Show involvement of activin family ligands in the occurrence of musculoskeletal derangements D. All of the above is correct

36 3- Males and females? A. Respond to cancer and chemotherapy in the same manner B. Present the same amount of trabecular bone C. Differ in the response to chemotherapy, in that the females are normally more resistant and show fewer toxicities D. None of the above is correct

37 4- Burn injury affects muscle and bone by? A. Causing a raise in the body temperature B. Determining persistently elevated inflammation C. Promoting muscle anabolism D. Increasing the body weight