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Wenhan Chang Ph.D.

Ionic and Hormonal Regulation of Skeletal Development and Repair

Wenhan Chang Ph.D.

My research is focused on the hormonal and ionic controls of mineral homeostasis and skeletal development using molecular, transgenic, and gene knockout approaches. Specifically, we study the actions of parathyroid hormone receptor (PTH1R), insulin-like growth factor-1 receptor (IGF1R), and the extracellular Ca2+-sensing receptor (CaSR) in tissues that control mineral metabolism and bone growth. We have generated mice with conditional ablation of the PTH1R, CaSR, or IGF1R genes in parathyroid glands (PTGs), kidney, intestine, cartilage, bone, skin, pituitary gland (Pit) and/or hypothalamus then examined their functional outcomes. We also developed primary cell/organ cultures to allow for genetic or pharmacological manipulations of the cell/organ in vitro for mechanistic studies.  Our data demonstrated that PTH1R, IGF1R, and CaSR play non-redundant roles in the growth, survival, and differentiation of chondrocytes and bones cells and eventually overall bone growth. We also unveiled distinct roles of the CaSR in modulating parathyroid hormonal secretion in PTGs, Ca2+ recycling in kidney, Ca2+ absorption in guts, keratinocyte differentiation in skin, and general growth and energy metabolism through CaSR actions in the Pit and hypothalamus. Research is ongoing to explore the mechanisms underlying the above actions. We have also begun to use some of the above animal models to investigate the role of the CaSR and IGF1R in the healing of bone fractures and the repair of cartilage injuries due to excess mechanical loading. There is the potential of using these receptors as new therapeutic targets for metabolic and skeletal diseases.

Selected publications:

Mamillapalli R, Vanhouten J, Dann P, Bikle D, Chang W, Brown E, Wysolmerski J. Mammary-Specific Ablation of the Calcium Sensing Receptor during Lactation alters Maternal Calcium Metabolism, Milk Calcium Transport and Neonatal Calcium Accrual. Endocrinology. 2013 Jun 19. 
View in: PubMed

Cheng Z, Liang N, Chen TH, Li A, Santa Maria C, You M, Ho H, Song F, Bikle D, Tu C, Shoback D, Chang W. Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca(2+) and parathyroid hormone in mice. J Bone Miner Res. 2013 May; 28(5):1087-100. 
View in: PubMed

Riccardi D, Brennan SC, Chang W. The extracellular calcium-sensing receptor, CaSR, in fetal development. Best Pract Res Clin Endocrinol Metab. 2013 Jun; 27(3):443-53. 
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Dvorak-Ewell MM, Chen TH, Liang N, Garvey C, Liu B, Tu C, Chang W, Bikle DD, Shoback DM. Osteoblast extracellular Ca2+ -sensing receptor regulates bone development, mineralization, and turnover. J Bone Miner Res. 2011 Dec; 26(12):2935-47. 
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Rey O, Chang W, Bikle D, Rozengurt N, Young SH, Rozengurt E. Negative cross-talk between calcium-sensing receptor and ß-catenin signaling systems in colonic epithelium. J Biol Chem. 2012 Jan 6; 287(2):1158-67. 
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Wang Y, Cheng Z, Elalieh HZ, Nakamura E, Nguyen MT, Mackem S, Clemens TL, Bikle DD, Chang W. IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway. J Bone Miner Res. 2011 Jul; 26(7):1437-46. 
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Chang W, Dvorak M, Shoback D. Assessing constitutive activity of extracellular calcium-sensing receptors in vitro and in bone. Methods Enzymol. 2010; 484:253-66. 
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Chang W, Tu C, Chen TH, Bikle D, Shoback D. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal. 2008; 1(35):ra1. 
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Cheng Z, Tu C, Rodriguez L, Chen TH, Dvorak MM, Margeta M, Gassmann M, Bettler B, Shoback D, Chang W. Type B gamma-aminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes. Endocrinology. 2007 Oct; 148(10):4984-92. 
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Dvorak MM, Chen TH, Orwoll B, Garvey C, Chang W, Bikle DD, Shoback DM. Constitutive activity of the osteoblast Ca2+-sensing receptor promotes loss of cancellous bone. Endocrinology. 2007 Jul; 148(7):3156-63. 
View in: PubMed