Basics of Bone Biology

Educational Objectives

The goal of this program is to improve management of osteoporosis using the concepts of bone biology. After hearing and assimilating this program, the clinician will be better able to:

1. Describe the role of chondrocytes, osteoblasts, osteoclasts, and osteocytes in bone growth and remodeling.
2. Identify paracrine and endocrine regulators of bone growth and remodeling.

Summary

Anatomy of long bones: epiphysis — includes a secondary ossification center; comprised of trabecular bone found underneath the articular cartilage; growth plate — located underneath the epiphysis and is responsible for the growth of bone during development; metaphysis — located below the epiphysis and is comprised of trabecular bone; diaphysis — comprised of cortical bone; periosteum — membrane on the outer surface of the diaphysis; endosteum — membrane on the inner surface; bone marrow — the innermost part of the bone

Formation of bone: the growth plate is a complex region that serves several functions; articular cartilage contains chondrocytes that remain undifferentiated unless a pathology (eg, osteoarthritis) develops; it also contains stem cells that differentiate into hypertrophic chondrocytes and can transdifferentiate into osteoblasts; osteoblasts also come from the perichondrium to form trabecular bone in the epiphysis; some of these cells go on into the diaphysis

Cortical bone: periosteum contains stem cells, which differentiate into osteoblasts; the endosteal surface also has stem cells; the Haversian canals are central to the lamellar bone and contain cells that help populate and form bone

Bone cell lineages: osteoblasts — originate from mesenchymal stem cells (also known as osteoprogenitor cells) and may differentiate into chondrocytes and adipocytes under specific hormonal regulation; the fates of the osteoblast are to create the lining cells of the bone, which are capable of being reactivated, or to differentiate into osteoclasts and be incorporated into the bone; osteoclasts — originate from hematopoietic progenitor cells and macrophages; involved in resorption of bone and die after they serve their function; the precursors fuse to form multinucleated osteoclasts

Signaling mechanisms in osteoclastogenesis: RANK ligand — a transmembrane protein expressed by osteoblasts; binds to RANK on the osteoclast precursors, which initiates osteoclastogenesis; osteoprotegerin — produced by osteoblasts; inhibits the RANK ligand by blocking its ability to interact with RANK on the osteoclast precursors; denosumab is an antibody that acts similarly to osteoprotegerin to inhibit osteoclastogenesis

Bone remodeling: in the resting phase, the osteocytes are quiescent; when the cell undergoes stress (eg, fracture or mechanical stress), the osteocytes activate the osteoclasts, which then resorb the bone; next, a reversal phase occurs in which the osteoclasts die, and preosteoblasts differentiate into functional osteoblasts that fill up the resorption pits left by the osteoclasts and produce an osteoid matrix, which is mineralized by osteoblasts to form bone; osteoporosis develops when the balance between bone resorption and bone formation is abnormal

Paracrine regulators of bone growth and remodeling: parathyroid hormone-related protein (PTHrP) — the first 13 amino acids in the N-terminal end are homologous to parathyroid hormone (PTH); the first 36 amino acids conduct PTH-like biologic activity; function of the midregion of the molecule is unclear, but it may be involved in transport of placental calcium or renal bicarbonate; the C-terminal portion is called osteostatin because it can inhibit bone resorption, although its function has not been well studied; expressed in the resting zone of the growth plate and slows the differentiation process; Indian hedgehog — expressed and secreted from prehypertrophic chondrocytes and promotes production of PTHrP; insulin-like growth factor-1 (IGF-1) — enhances the proliferation of chondrocytes and stimulates their differentiation into prehypertrophic and hypertrophic chondrocytes; can inhibit the production of PTHrP

Endocrine regulators of bone growth and remodeling

Parathyroid hormone: PTHrP and PTH work through the same transmembrane receptor; downstream signaling players include cyclic AMP, diacylglycerol (activates protein kinase C), IP3 (regulates calcium release from the endoplasmic reticulum), and calcium; depending on the cell, these play more or less dominant roles; in excess, PTH stimulates the release of calcium phosphate from bone; it can promote bone formation as well as bone resorption; in the kidneys, it increases calcium resorption from the distal tubules and promotes excretion of phosphate from the proximal tubules; PTH promotes the synthesis of 1,25-dihydrocholecalciferol, which enhances the absorption of calcium and phosphate in the small intestine

Fibroblast growth factor-23 (FGF23): phosphatonin that regulates phosphate; decreases the number of the sodium-phosphate transporters in the proximal tubule, which decreases phosphate reabsorption from the kidney and leads to hypophosphatemia; inhibits the production of 1,25-dihydrocholecalciferol; some diseases that are associated with low phosphate, eg, X-linked hyperphosphatemia, are due to excess FGF23; requires a co-receptor along with the FGF receptor

Insulin-like growth factors: regulate bone formation and resorption (especially IGF-1); they are required for PTH action; there are 6 IGF binding proteins that bind with and regulate activity of IGFs and also have independent actions; several receptors bind to IGF; the main IGF-1 receptor to which both IGF-1 and IGF-2 bind is a tetramer, but it can also hybridize as a dimer with the insulin receptor and modify the actions of insulin and IGF-1; the type 2 IGF-1 receptor binds to the IGFs (particularly IGF-2) but does not signal

Signaling pathways for IGFs: include the Ras-MAPK pathway and the PI3K pathway (which has several steps following the activation of Akt by PI3K); the combination of these pathways varies among cells; bioactivities include cell growth, differentiation, survival, and protein synthesis; knockout of IGF-1 or IGF-1 receptor in animal models reduces bone formation, and PTH no longer has an effect

Role of ephrins: have bidirectional signaling; these molecules are regulated by IGF-1 and are required for the actions of IGF-1 and PTH on bone; EPHB4 receptor is a transmembrane receptor with a kinase domain that regulates signaling molecules; activation of ephrin-B2 by the EPHB4 receptor is important for regulation of osteoclasts and osteoblasts

Readings

Arthur A, Gronthos S. Eph-ephrin signaling mediates cross-talk within the bone microenvironment. Front Cell Dev Biol. 2021; 9:598612; doi: 10.3389/fcell.2021.598612; Hakuno F, Takahashi SI. 40 years of IGF1: IGF1 receptor signaling pathways. J Mol Endocrinol. 2018; 61:T69-T86; doi: 10.1530/JME-17-0311; Han Y, You X, Xing W, et al. Paracrine and endocrine actions of bone — the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res. 2018; 6:16; doi: 10.1038/s41413-018-0019-6; Park-Min KH. Mechanisms involved in normal and pathological osteoclastogenesis. Cell Mol Life Sci. 2018; 75:2519-2528; doi: 10.1007/s00018-018-2817-9; Pathria MN, Chung CB, Resnick DL. Acute and stress-related injuries of bone and cartilage: pertinent anatomy, basic biomechanics, and imaging perspective. Radiology. 2016; 280:21-38; doi: 10.1148/radiol.16142305; Tsang KY, Chan D, Cheah KSE. Fate of growth plate hypertrophic chondrocytes: death or lineage extension? Dev Growth Differ. 2015; 57:179-192; doi: 10.1111/dgd.12203.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Bikle received a grant from Radius Pharmaceuticals Inc. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Bikle was recorded at the 18th Annual Osteoporosis: New Insights in Research, Diagnosis and Clinical Care, held virtually on July 16, 2021, and presented by the University of California, San Francisco, School of Medicine. For information on future CME activities from this presenter, please visit Meded.ucsf.edu/continuing-education. Audio Digest thanks the speakers and the University of California, San Francisco, School of Medicine for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

OR450701

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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