Integration Lecture #1 Claudia Stanescu, Ph.D. Office hours: Tue 10-12, Thurs 2-3Final exam format • 40 multiple choice questions (4 pts each) • 10 questions from the two integration lectures • 30 questions from the rest of the course lectures focusing on the objectives listed in the study guide (posted on D2L)Integration lecture objectives: 1) Apply knowledge gained in this course to physiological scenarios / problems 2) Integrate information across organ systemsCollagen- Mineral Organization Nair AK, et al. Molecular mechanisms of mineralized collagen fibrils in bone. Nature communications, 2013. Hambli R and Barkaoui A. Journal of Theoretical Biology 301 (2012) 28-41. Collagen microfibril Minerals deposited in spaces between collagen molecules1. ACTIVATION: preosteoclasts are stimulated and differentiate under the influence of cytokines and growth factors into mature active osteoclasts 2. RESORPTION: osteoclasts digest mineral matrix (old bone) Bone Remodeling 3. REVERSAL: end of resorption; recruitment of osteoblasts 4. FORMATION: osteoblasts synthesize new bone matrix 5. QUIESCENCE: osteoblasts become resting bone lining cells on the newly formed bone surface /www.iofbonehealth.org/ 4 monthsMajor Bone Diseases Osteoporosis – Decreased bone mass and density that causes thinning of bones and increased risk of fracture; normal ratio of bone mineral to matrix; usually not associated with pain unless fracture occurs; diagnosed with bone scan and usually not detectable with blood tests Osteomalacia – Decreased mineralization of newly formed bone matrix at sites of bone remodeling as a consequence of Ca2+ deficiency (due to Vit.D deficiency); associated with achy bone pain Osteogenesis Imperfecta – Congenital disorder that affects production of type I collagen due to genetic mutation; brittle bones that fracture easily, often in childhood or adolescence; pain associated with fracturesProblem #1 • Ms. Lopez is a 47 year old woman experiencing hip pain • She tripped and fell earlier today and landed on her buttocks • She has a history of low bone density but never had a single bone fractureBased on the patient information, which of the following diseases could you rule out and why? 1. Osteoporosis 2. Osteomalacia 3. Osteogenesis imperfecta Please discuss this in groups of 3-4Major Bone Diseases Osteoporosis – Decreased bone mass and density that causes thinning of bones and increased risk of fracture; normal ratio of bone mineral to matrix; usually not associated with pain unless fracture occurs; diagnosed with bone scan and usually not detectable with blood tests Osteomalacia – Decreased mineralization of newly formed bone matrix at sites of bone remodeling as a consequence of Ca2+ deficiency (due to Vit.D deficiency); associated with achy bone pain Osteogenesis Imperfecta – Congenital disorder that affects production of type I collagen due to genetic mutation; brittle bones that fracture easily often in childhood or adolescence; pain associated with fracturesBased on the patient history, which of the following diseases could you rule out? A. Osteoporosis B. Osteomalacia C. Osteogenesis imperfecta A. B. C.54%25%21%More about Ms. Lopez… History: celiac disease, hip pain for months, skin cancer fear Blood tests: mostly normal except Calcium: 7.1 mg/dl (8.6-10.6 mg/dl) 25-hydroxy vitamin D: 9 ng/ml (30-80 ng/ml) Parathyroid hormone: 120 pg/ml (15-75 pg/ml) Imaging: Low bone density (DXA) and “pseudofracture” present in femur neckBased on the patient history and the labs and imaging, what is your diagnosis and why? 1. Osteoporosis 2. Osteomalacia Please discuss in groups of 3-4More about Ms. Lopez… History: celiac disease, hip pain for months, skin cancer fear Blood tests: mostly normal except Calcium: 7.1 mg/dl (8.6-10.6 mg/dl) 25-hydroxy vitamin D: 9 ng/ml (30-80 ng/ml) Parathyroid hormone: 120 pg/ml (15-75 pg/ml) Imaging: Low bone density (DXA) and “pseudofracture” present in femur neckBased on the patient history and the labs and imaging, what is your final diagnosis? A. Osteoporosis B. Osteomalacia A. B.91%9%More about Ms. Lopez… History: celiac disease, hip pain for months, skin cancer fear Blood tests: mostly normal except Calcium: 7.1 mg/dl (8.6-10.6 mg/dl) 25-hydroxy vitamin D: 9 ng/ml (30-80 ng/ml) Parathyroid hormone: 120 pg/ml (15-75 pg/ml) Imaging: Low bone density (DXA) and “pseudofracture” present in femur neckVitamin D pathway Vitamin D precursor 7-dehydrocholesterol Dietary Vitamin D3 Cholecalciferol Vitamin D3 Cholecalciferol Fish oil, Egg yolks, Milk UV Light 25-hydroxy- Cholecalciferol (Calcidiol) 1,25 dihydroxy- cholecalciferol (Calcitriol) Active form + Blood Liver Kidney + + PTH Low Blood Calcium Blood Skin Blood Intestine Vitamin D is converted to the active form only if PTH present or Ca is low in the blood SkinDiscussion Osteomalacia: vitamin D is low because of poor absorption in the intestine and because the patient is afraid of the sun. Low vitamin D leads to calcium deficiency  leads to release of PTH in an effort to increase the calcium levels in the blood. PTH can stimulate calcium release from bones (hence low bone density everywhere) but cannot stimulate absorption of calcium from intestine without vitamin D. Despite PTH presence, serum calcium is still low because there is an absolute requirement for calcium from the diet to maintain calcium levels. Osteoporosis: Why are the blood tests normal in osteoporosis? Patients do not experience pain with osteoporosis (usually asymptomatic). With osteoporosis, bone resorption is greater than bone formation. However, bone remodeling cycles last 4 months and the release of calcium from bone is slow. This may increase the blood and urine calcium slightly but not fast enough to be detected in a blood test (values may be on the high end of normal). ‘Pseudofractures’ are not seen in osteoporosis.Problem #1 Take Home Message 1) Deficiency of collagen or minerals in bone can lead to decreased bone strength; understanding the role of each component in bone strength can help you understand different bone disorders 2) Osteoporosis does not usually present with pain; serum calcium, vitamin D and parathyroid hormone are usually normal 3) Low bone density does not always mean osteoporosis; patient history and lab work are needed to rule out other conditionsProblem #2 Effect of exercise on muscle Muscle will change in response to the stresses it encounters