Wenhan Chang, PhD

Adjunct Professor
Meicine
+1 415 575-0558

My research investigates the roles of the extracellular Ca2+, gama-aminobutyric acid (GABA), insulin-like growth factor-1 (IGF1), parathyroid hormone (PTH), FGF23, and vitamin D, and their respective receptors (CaSR, GABBR1, IGF1R, PTH1R, Klotho, and VDR) in (1) controlling mineral homeostasis; (2) mediating skeletal development and facture healing; (3) regulating neuroendocrine functions; and (4) neuroprotection. We study mice with conditional knockout (KO) of genes encoding CaSR, GABBR1, IGF1, IGF1R, PTH1R, Cyp27b1, FGF23, Klotho, VDR, and their associated signaling molecules in parathyroid cells (PTC), intestinal epithelial cells, renal tubule cells, chondrocytes, bone cells, and/or neurons to determine their biological functions. These in vivo studies are complemented with in vitro cell/organ cultures of parathyroid cells/glands; primary intestinal and renal tubular cells and associated cell lines; primary chondrocyte, osteoblast, osteoclast, and related cell lines; and neurons to further delineate the underlying mechanisms. We perform union and nonunion bone fractures on the above KO mice and study the structural, biochemical, and biomechanics properties of the resulting callus to determine the functions of the CaSR, GABBR1, IGF1, IGF1R, PTH1R, Cyp27b1, VDR, and their associated signaling molecules in fracture healing. Based on the above study, we are developing new pharmacological regimens for more robust skeletal anabolism to treat osteoporosis and to repair bone. We also perform brain ischemia and traumatic brain injury protocols on the KO mice to assess the role of those molecules in the development of neuronal injury and to develop new therapies for neuroprotection against ischemia- and TBI-induced brain injury.
Dr. Chang is also the director of the SF-VAMC Bone Imaging Core facility.

Interests: Ionic and hormonal regulation of skeletal development and repair
 

Publications: 

FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

JCI insight

Courbon G, Kentrup D, Thomas JJ, Wang X, Tsai HH, Spindler J, Von Drasek J, Ndjonko LM, Martinez-Calle M, Lynch S, Hivert L, Wang X, Chang W, Feng JQ, David V, Martin A

Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation.

Blood

Courbon G, Thomas JJ, Martinez-Calle M, Wang X, Spindler J, Von Drasek J, Hunt-Tobey B, Mehta R, Isakova T, Chang W, Creemers JWM, Ji P, Martin A, David V

Immune Reconstitution Bone Loss Exacerbates Bone Degeneration Due to Natural Aging in a Mouse Model.

The Journal of infectious diseases

Weitzmann MN, Weiss D, Vikulina T, Roser-Page S, Yu K, McGee-Lawrence ME, Tu CL, Chang W, Ofotokun I

Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells.

Journal of the American Society of Nephrology : JASN

Schepelmann M, Ranieri M, Lopez-Fernandez I, Webberley TS, Brennan SC, Yarova PL, Graca J, Hanif UK, Müller C, Manhardt T, Salzmann M, Quasnichka H, Price SA, Ward DT, Gilbert T, Matchkov VV, Fenton RA, Herberger A, Hwong J, Santa Maria C, Tu CL, Kallay E, Valenti G, Chang W, Riccardi D

Precise druggability of the PTH type 1 receptor.

Nature chemical biology

Sutkeviciute I, Lee JY, White AD, Maria CS, Peña KA, Savransky S, Doruker P, Li H, Lei S, Kaynak B, Tu C, Clark LJ, Sanker S, Gardella TJ, Chang W, Bahar I, Vilardaga JP

Spatial bias in cAMP generation determines biological responses to PTH type 1 receptor activation.

Science signaling

White AD, Peña KA, Clark LJ, Maria CS, Liu S, Jean-Alphonse FG, Lee JY, Lei S, Cheng Z, Tu CL, Fang F, Szeto N, Gardella TJ, Xiao K, Gellman SH, Bahar I, Sutkeviciute I, Chang W, Vilardaga JP

FBW7 couples structural integrity with functional output of primary cilia.

Communications biology

Petsouki E, Gerakopoulos V, Szeto N, Chang W, Humphrey MB, Tsiokas L

The mTORC2 Regulator Homer1 Modulates Protein Levels and Sub-Cellular Localization of the CaSR in Osteoblast-Lineage Cells.

International journal of molecular sciences

Rybchyn MS, Brennan-Speranza TC, Mor D, Cheng Z, Chang W, Conigrave AD, Mason RS

Calcium-sensing receptor and CPAP-induced neonatal airway hyperreactivity in mice.

Pediatric research

Mayer CA, Roos B, Teske J, Wells N, Martin RJ, Chang W, Pabelick CM, Prakash YS, MacFarlane PM

Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling.

Scientific reports

Egli-Spichtig D, Zhang MYH, Li A, Pastor Arroyo EM, Hernando N, Wagner CA, Chang W, Perwad F

Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis.

Nature communications

Jäger E, Murthy S, Schmidt C, Hahn M, Strobel S, Peters A, Stäubert C, Sungur P, Venus T, Geisler M, Radusheva V, Raps S, Rothe K, Scholz R, Jung S, Wagner S, Pierer M, Seifert O, Chang W, Estrela-Lopis I, Raulien N, Krohn K, Sträter N, Hoeppener S, Schöneberg T, Rossol M, Wagner U

Control of PTH secretion by the TRPC1 ion channel.

JCI insight

Onopiuk M, Eby B, Nesin V, Ngo P, Lerner M, Gorvin CM, Stokes VJ, Thakker RV, Brandi ML, Chang W, Humphrey MB, Tsiokas L, Lau K

PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism.

Nature metabolism

Chang W, Tu CL, Jean-Alphonse FG, Herberger A, Cheng Z, Hwong J, Ho H, Li A, Wang D, Liu H, White AD, Suh I, Shen W, Duh QY, Khanafshar E, Shoback DM, Xiao K, Vilardaga JP

Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney.

The Journal of clinical investigation

Simic P, Kim W, Zhou W, Pierce KA, Chang W, Sykes DB, Aziz NB, Elmariah S, Ngo D, Pajevic PD, Govea N, Kestenbaum BR, de Boer IH, Cheng Z, Christov M, Chun J, Leaf DE, Waikar SS, Tager AM, Gerszten RE, Thadhani RI, Clish CB, Jüppner H, Wein MN, Rhee EP

Calcium-Sensing Receptors in Chondrocytes and Osteoblasts Are Required for Callus Maturation and Fracture Healing in Mice.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Cheng Z, Li A, Tu CL, Maria CS, Szeto N, Herberger A, Chen TH, Song F, Wang J, Liu X, Shoback DM, Chang W

Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion.

Nature communications

Centeno PP, Herberger A, Mun HC, Tu C, Nemeth EF, Chang W, Conigrave AD, Ward DT

Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent ß-catenin stabilization in osteoblasts.

The Journal of biological chemistry

Rybchyn MS, Islam KS, Brennan-Speranza TC, Cheng Z, Brennan SC, Chang W, Mason RS, Conigrave AD

Myosin 1a Regulates Osteoblast Differentiation Independent of Intestinal Calcium Transport.

Journal of the Endocrine Society

Munson S, Wang Y, Chang W, Bikle DD

Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Zhang M, Yang H, Wan X, Lu L, Zhang J, Zhang H, Ye T, Liu Q, Xie M, Liu X, Yu S, Guo S, Chang W, Wang M

The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases.

Nature reviews. Endocrinology

Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV

Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes.

Development (Cambridge, England)

Hu DP, Ferro F, Yang F, Taylor AJ, Chang W, Miclau T, Marcucio RS, Bahney CS

Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone-Related Protein.

Cancer research

Kim W, Takyar FM, Swan K, Jeong J, VanHouten J, Sullivan C, Dann P, Yu H, Fiaschi-Taesch N, Chang W, Wysolmerski J

Sprouty2 regulates endochondral bone formation by modulation of RTK and BMP signaling.

Bone

Joo A, Long R, Cheng Z, Alexander C, Chang W, Klein OD

Calcium Sensing Receptor Function Supports Osteoblast Survival and Acts as a Co-Factor in PTH Anabolic Actions in Bone.

Journal of cellular biochemistry

Al-Dujaili SA, Koh AJ, Dang M, Mi X, Chang W, Ma PX, McCauley LK

Unilateral anterior crossbite induces aberrant mineral deposition in degenerative temporomandibular cartilage in rats.

Osteoarthritis and Cartilage

Zhang M, Wang H, Zhang J, Zhang H, Yang H, Wan X, Jing L, Lu L, Liu X, Yu S, Chang W, Wang M

Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism.

Seminars in cell & developmental biology

Santa Maria C, Cheng Z, Li A, Wang J, Shoback D, Tu CL, Chang W

Comparative expression of the extracellular calcium-sensing receptor in the mouse, rat, and human kidney.

American journal of physiology. Renal physiology

Graca JA, Schepelmann M, Brennan SC, Reens J, Chang W, Yan P, Toka H, Riccardi D, Price SA

The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure.

American journal of physiology. Cell physiology

Schepelmann M, Yarova PL, Lopez-Fernandez I, Davies TS, Brennan SC, Edwards PJ, Aggarwal A, Graça J, Rietdorf K, Matchkov V, Fenton RA, Chang W, Krssak M, Stewart A, Broadley KJ, Ward DT, Price SA, Edwards DH, Kemp PJ, Riccardi D

Role of IGF-I signaling in muscle bone interactions.

Bone

Bikle DD, Tahimic C, Chang W, Wang Y, Philippou A, Barton ER

Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Wang T, Wang Y, Menendez A, Fong C, Babey M, Tahimic CG, Cheng Z, Li A, Chang W, Bikle DD

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma.

Science translational medicine

Yarova PL, Stewart AL, Sathish V, Britt RD, Thompson MA, P Lowe AP, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang W, Bin Khayat ME, Ward DT, Corrigan CJ, T Ward JP, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D

Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon.

American journal of physiology. Gastrointestinal and liver physiology

Tang L, Peng M, Liu L, Chang W, Binder HJ, Cheng SX

The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon.

Molecular cancer

Aggarwal A, Prinz-Wohlgenannt M, Gröschel C, Tennakoon S, Meshcheryakova A, Chang W, Brown EM, Mechtcheriakova D, Kállay E

Wnt5a/Ror2 mediates temporomandibular joint subchondral bone remodeling.

Journal of dental research

Yang T, Zhang J, Cao Y, Zhang M, Jing L, Jiao K, Yu S, Chang W, Chen D, Wang M

Calcium-sensing receptor (CaSR) as a novel target for ischemic neuroprotection.

Annals of clinical and translational neurology

Kim JY, Ho H, Kim N, Liu J, Tu CL, Yenari MA, Chang W

Ephrin B2/EphB4 mediates the actions of IGF-I signaling in regulating endochondral bone formation.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Wang Y, Menendez A, Fong C, ElAlieh HZ, Chang W, Bikle DD

Disrupted bone remodeling leads to cochlear overgrowth and hearing loss in a mouse model of fibrous dysplasia.

PloS one

Akil O, Hall-Glenn F, Chang J, Li A, Chang W, Lustig LR, Alliston T, Hsiao EC

Joint instability and cartilage compression in a mouse model of posttraumatic osteoarthritis.

Journal of orthopaedic research : official publication of the Orthopaedic Research Society

Onur TS, Wu R, Chu S, Chang W, Kim HT, Dang AB

Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

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

The extracellular calcium-sensing receptor, CaSR, in fetal development.

Best practice & research. Clinical endocrinology & metabolism

Riccardi D, Brennan SC, Chang W

Ablation of the calcium-sensing receptor in keratinocytes impairs epidermal differentiation and barrier function.

The Journal of investigative dermatology

Tu CL, Crumrine DA, Man MQ, Chang W, Elalieh H, You M, Elias PM, Bikle DD

Osteoblast extracellular Ca2+ -sensing receptor regulates bone development, mineralization, and turnover.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Dvorak-Ewell MM, Chen TH, Liang N, Garvey C, Liu B, Tu C, Chang W, Bikle DD, Shoback DM

Negative cross-talk between calcium-sensing receptor and ß-catenin signaling systems in colonic epithelium.

The Journal of biological chemistry

Rey O, Chang W, Bikle D, Rozengurt N, Young SH, Rozengurt E

IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Wang Y, Cheng Z, Elalieh HZ, Nakamura E, Nguyen MT, Mackem S, Clemens TL, Bikle DD, Chang W

Naturally-occurring mutation in the calcium-sensing receptor reveals the significance of extracellular domain loop III region for class C G-protein-coupled receptor function.

The Journal of clinical endocrinology and metabolism

Dong Q, Cheng Z, Chang W, Blackman BE, Conte FA, Hu J, Shoback D, Miller WL

Type B gamma-aminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes.

Endocrinology

Cheng Z, Tu C, Rodriguez L, Chen TH, Dvorak MM, Margeta M, Gassmann M, Bettler B, Shoback D, Chang W

Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons.

The Journal of biological chemistry

Chang W, Tu C, Cheng Z, Rodriguez L, Chen TH, Gassmann M, Bettler B, Margeta M, Jan LY, Shoback D

Constitutive activity of the osteoblast Ca2+-sensing receptor promotes loss of cancellous bone.

Endocrinology

Dvorak MM, Chen TH, Orwoll B, Garvey C, Chang W, Bikle DD, Shoback DM

Insulin-like growth factor-I is essential for embryonic bone development.

Endocrinology

Wang Y, Nishida S, Sakata T, Elalieh HZ, Chang W, Halloran BP, Doty SB, Bikle DD

Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes.

The Journal of investigative dermatology

Tu CL, Chang W, Bikle DD

Extracellular Ca2+-sensing in cartilage.

Journal of musculoskeletal & neuronal interactions

Chang W, Rodriguez L, Chen TH, Tu C, Shoback D

Epidermal expression of the full-length extracellular calcium-sensing receptor is required for normal keratinocyte differentiation.

Journal of cellular physiology

Komuves L, Oda Y, Tu CL, Chang WH, Ho-Pao CL, Mauro T, Bikle DD

Parathyroid cells express dihydropyridine-sensitive cation currents and L-type calcium channel subunits.

American journal of physiology. Endocrinology and metabolism

Chang W, Pratt SA, Chen TH, Tu CL, Mikala G, Schwartz A, Shoback D

The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation.

The Journal of biological chemistry

Oda Y, Tu CL, Chang W, Crumrine D, Kömüves L, Mauro T, Elias PM, Bikle DD

Protein kinase C activation blocks calcium receptor signaling in Xenopus laevis oocytes.

Molecular and cellular endocrinology

Chang W, Pratt S, Chen TH, Shoback D

Expression and signal transduction of calcium-sensing receptors in cartilage and bone.

Endocrinology

Chang W, Tu C, Chen TH, Komuves L, Oda Y, Pratt SA, Miller S, Shoback D

Calcium sensing in cultured chondrogenic RCJ3.1C5.18 cells.

Endocrinology

Chang W, Tu C, Bajra R, Komuves L, Miller S, Strewler G, Shoback D

Regulation of extracellular calcium-activated cation currents by cAMP in parathyroid cells.

The American journal of physiology

Chang W, Chen TH, Pratt S, Shoback D

Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in mammalian cells and Xenopus laevis oocytes and immunodetection of receptor protein by region-specific antipeptide antisera.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Chang W, Pratt S, Chen TH, Nemeth E, Huang Z, Shoback D

Parathyroid Ca(2+)-conducting currents are modulated by muscarinic receptor agonists and antagonists.

The American journal of physiology

Chang W, Chen TH, Pratt SA, Yen B, Fu M, Shoback D

[Acute hepatic porphyria and its neurological syndrome].

Schweizerische medizinische Wochenschrift

Bont A, Steck AJ, Meyer UA

Regulation of Ca(2+)-conducting currents in parathyroid cells by extracellular Ca(2+) and channel blockers.

The American journal of physiology

Chang W, Chen TH, Gardner P, Shoback D