Periosteum: Definition, Physiology, Origins, Growth Regulation, Cells, Fracture Repair and Bone Modeling

It is a fragile region of non-calcified tissue outside the bones.

It covers the entire surface of all the bones in the body, except the ends of the bones that make up the joints, where cartilage forms the outer layer of bone.

The periosteum consists of an outer layer of fibrous connective tissue and an inner osteogenic layer. The fibrous cap is dense, irregular connective tissue that contains many strong collagen fibers and fibroblasts.

Fibroblasts produce collagen fibers and regenerate the fibrous layer as it wears out over time or is injured by stress in the body. The osteogenic layer contains many stem cells and osteoblastic cells that line the surface of the bone tissue that constitutes the hard part of the bone.

Osteoblasts absorb calcium to form the mineral matrix of solid bone.


The fibrous layer of the periosteum plays a vital role in connecting the bones to the rest of the body.

The collagen fibers of the periosteum not only wrap around the entire bone but also fuse with the collagen fibers of the ligaments, joint capsules, and tendons that connect to the bone.


Thus, a continuous mass of collagen extends from the surface of each bone through the joints, ligaments, and joint capsule to adjacent bones.

Similarly, collagen extends from the periosteum to the tendons; it extends around and through the muscles like the muscle fascia and attaches to another bone.

The periosteum also plays a vital role in the growth and maintenance of bones. Throughout life, bones are constantly being remodeled to adjust their size and thickness to the body’s demands and the availability of calcium to form bone.

As bones grow, most of this growth is produced by osteoblast cells in the periosteum, which absorb calcium ions from the blood and have a complex mineral matrix.

When bones are fractured or microscopically damaged by stress, periosteal osteoblasts repair this damage and replace the mineral matrix, often strengthening the bone beyond its original thickness.

Origins of the periosteum and growth regulation

The periosteum arises as a condensation of general mesenchyme that forms a perichondrial sheath around the cartilage ring during development. It ends in the joint space, creating a perichondrial ring around the end of the cartilage model where the epiphyseal cartilage will develop.

As bone develops, osteoblast progenitor cells differentiate into osteoblasts in the deep layers of the periosteum, contributing to the mineralization of a bony ring, and ultimately to the enlargement of the bone diaphysis, the apposition of new bone by ossification. Intramembranous.

The periosteum is continuous with Sharpey’s fibers that insert into the bone and hold it firmly, although the strength and size of these connections reduce with age. The periosteum is thought to be classified into tendons and ligaments as they insert into the bone, but there is still some debate on this.

The complete periosteum is 70 μm to 150 μm in growing individuals, but it thins with age as growth and appositional formation increase. It is generally thickest near the metaphysis and thinner on the shaft.

The periosteum in the adult is composed of two layers, an outer fibrous covering of axially aligned collagen fibers that contain both fibroblasts and mesenchymal cells and is composed of type I, III, VI collagens, and elastin.

Type III collagen is found in abundance in blood vessels. It may reflect vascularization of the periosteum, but because it rapidly cross-links, it may also work to reduce tissue extensibility and improve stability.

The inner osteogenic layer or “cambium” contributes to the appositional growth of bone throughout life. It includes mesenchymal stem cells, osteoblasts, and endothelial pericytes, which probably provide an additional set of osteoprogenitor cells.

It is also possible that some of the cells in the fibrous portion migrate to the cambium layer and contribute to bone formation.

The osteoblasts in this layer are connected by their cellular processes to the osteocytes within the bone. Some have suggested an elastic intermediate layer containing capillaries, but this may disappear with maturity.

Whether this constitutes another layer or not, it is true that the periosteum is highly vascularized and highly innervated by sympathetic and sensory fibers.

During growth, the periosteum migrates to cover new bone as it grows lengthwise. This migration involves the cell layer as well as the outer fibrous layer.

There is some evidence that the insertion of the periosteum into bone mineralized by Sharpey’s fibers helps regulate the longitudinal growth of the bone by restricting it and that the release of the periosteum allows for additional development.

This is presumed to be a physical process because the periosteal membrane is pre-stressed and physically retracts and shortens approximately three times when an incision is made from the bone. However, the stress generated by the fibrous periosteum and its attachments in bone is insufficient for physical restraint.

The most recent evidence suggests that restriction may occur through cell-regulated mechanotransduction pathways that detect intracellular tension and promote the release of soluble inhibitory factors by periosteal cells.

When the periosteum is released, bone morphogenetic proteins such as BMP-2 and BMP-4 are produced, stimulating a proliferative reaction that causes growth.

Periosteal cells

In its different layers, the periosteum contains a complete heterogeneous mix of skeletal cell types at various stages of lean development, from mesenchymal stem cells to chondrocytes, fibroblasts, and cells from across the osteoblastic lineage.

This explains its broad potential to create and shape bone throughout growth and its usefulness as a source of cells for orthopedic procedures, such as the rejuvenation of cartilage surfaces in degenerative joints.

Cells in the cambial layer of the periosteum are highly osteogenic and respond to mechanical stimulation, infection, and tumors.

They are highly proliferative and capable of forming highly organized laminated bone or highly disorganized tissue bone in pathological situations because mesenchymal cells are also present.

However, cells in the deep layer of the periosteum can also differentiate into chondroblasts and form cartilage, especially in adults, during the fracture healing process.

The diversity of tissue formation potential in this area is critically important during fracture healing.

Cells in the cambium layer of the periosteum express markers for both osteogenic and chondrogenic lineages.

Like progenitors and fully differentiated bone and cartilage cells at other locations, these cells also respond to regulation by a wide range of growth factors and other proteins.

Perhaps most prominently, transforming growth factor-beta (FCT-β) promotes chondrogenic activity but may inhibit the differentiation of osteoblast progenitors. Morphogenic proteins derived from cartilage (PMDC) are also known to drive periosteal cells to the chondrogenic pathway.

While both PMDC and parathyroid hormone-related protein, the latter in response to the Indian hedgehog expressed by hypertrophic chondrocytes, can contribute to the regulation of chondrocytes during the early stages of growth or in the healing of fractures.

Bone morphogenetic proteins, especially BMP-2 and BMP-4, can promote the proliferation and differentiation of osteogenic cells and are known to be expressed particularly during fracture healing. BMP-7 is expressed during periods of endochondral ossification, both in growth and in fracture healing.

Although osteoclasts are derived from blood rather than bone, the modeling of bone during growth requires the presence of cells that can become osteoclasts.

The periosteum is highly vascular, and these vessels can carry monocytes found in the mesenchyme of the developing limb.

Type IV collagenase, which is a marker for preosteoclast development, has become immunolocalized within the deep, fibrous layers of the periosteum.

Osteoclasts are thought to migrate from the more superficial layers of the periosteum through the deeper layers to the surface of the bone, where they can begin to shape the bone.

This migration is prevented by FCT-β and by matrix metalloproteinases, again suggesting an antagonistic relationship between chondrogenic and osteogenic processes during growth.

Periostin is an essential developmental protein that, in skeletal tissues, is localized to the periosteal membrane and the periodontal ligament. It is an intriguing but not yet well-understood candidate for regulating cellular processes within the periosteum and controlling the osteogenic potential of the periosteum.

Periostin regulates cell adhesion and recruitment and can be either a positive or negative regulator of osteoblast differentiation.

Periostin has a variety of isoforms; not all are located in the exact location or behave in the same way, so its role in regulating cell differentiation and bone formation is a complex issue.

A periostin-like factor (FSP) has been detected during embryogenesis in mesenchymal cells in the periosteum and osteoblasts throughout the trabecular bone. On this site, the periostin protein itself is not found.

On the other hand, FSP accelerates the differentiation of precursors into functioning osteoblasts and promotes bone formation, which may be different from the action of periostin.

Furthermore, FSP is upregulated during fracture repair, whereas periostin appears to regulate the mineralization of the newly formed callus negatively.

Thus, periostin probably prevents differentiation of osteoblasts and reduces bone formation, while its isoform promotes differentiation and osteogenesis.

Although the number of osteogenic cells in the cambium layer decreases with age, this appears to have little effect on their ability to respond to a mechanical stimulus. It is well known that periosteal apposition of bone continues throughout life, partially compensating for bone loss from other surfaces.

A significant reduction of cells in the periosteal cambium layer in animal models is associated with reduced chondrogenesis with age. Still, it is known that the potential to heal a fracture does not decrease with age in humans in the absence of other metabolic abnormalities.

The periosteal role in fracture repair

The periosteum plays a central and multifaceted role in fracture repair processes. The plethora of mesenchymal stem cells can differentiate into osteoblasts or chondroblasts under the multiple molecular signals released during the initial stage of inflammatory repair.

The periosteum thus participates both in intramembranous bone formation and in the processes of endochondral formation and ossification that occur during the healing process.

The healing of bone fractures is commonly described as divided into four stages:

An inflammatory stage, during which a hematoma forms and the initial molecular signals for repair are generated; periosteal formation of woven bone, which joins and stabilizes the fracture gap; cartilage formation and endochondral ossification; and finally, bone remodeling to return the bone to its original lamellar structure and its external shape.

The initial inflammatory stage incorporates a hematoma that extends into the periosteum and stimulates the proliferation of periosteal osteoprogenitors in the first two days.

Initially, this may be under the stimulus of insulin-like growth factor and its receptors, which are sensitive to inflammatory mediators in the hematoma. They are upregulated in the cambium layer of the periosteum within 24 hours of the fracture.

By day 3, the proliferative response is at its peak, concurrent with the expression of BMP-2, 3, 4, and 5,8 within the periosteum. There is also an early regulation (within three days) of the periostin during fracture healing.

Subsequently, the compromised progenitor cells of the periosteum migrate and differentiate between beginning to form tissue bone within millimeters of the fracture site. This process finally creates a bridge between the two ends of the broken bone and includes a cortical collar that will later be reshaped.

Bone modeling, remodeling, and periosteal apposition

Although the periosteal membrane thins and becomes less cellular with age, it maintains the ability to the apposition of new lamellar bone throughout life.

The periosteum is highly mechanosensitive, and the osteo- and chondroprogenitor pluripotent cells that reside in it are more mechanically sensitive even than mesenchymal stem cells.

Periosteal apposition occurs in both men and women as they age. However, the amount of apposition in women is insufficient to compensate for the significant loss of bone from the trabecular and endocortical compartments or to maintain premenopausal bone strength.

It has been an adage for years that the periosteal surface of the bone is immune to bone resorption or coupled remodeling, except perhaps during modeling processes near the bone metaphysis during growth.

Although it is true that during most of adult life, periosteal bone is more osteogenic than resorption, remodeling that involves resorption occurs on this surface, particularly in older people.

It is not difficult to find erosion cavities on the surface of the femur, for example, in people in their ninth decade. This is likely part of the adaptive process of a lifetime.

The periosteum is highly sensitive to various hormones but often responds differently from other bone envelopes (e.g., endocortical, trabecular, and intracortical).

During the growth and maturation period, the periosteal surface of the bone is susceptible to growth hormone and IGF-I, which promote appositional growth during development.

However, estrogens and androgens are also essential influences on appositional growth, both before and after puberty, and both are probably required for periosteal expansion.

Androgens stimulate periosteal apposition in both sexes, but low estrogen levels increase the sensitivity of androgens on the periosteal surface, even in males.

This may be why aromatase-deficient children with normal androgen levels have smaller bones. This interaction of estrogens and androgens in the periosteal apposition can persist throughout life.

It is well documented that postmenopausal estrogen deficiency is associated with periosteal apposition, and estrogen supplementation reduces expansion. However, it is unclear whether this is a direct effect of estrogen or an automatic compensation for bone loss on the endocortical surface.

However, the picture is complicated by the presence of two estrogen receptor (ER) subtypes, ER-α and ER-β, that can be antagonistic. Some animal experiments suggest that the interaction of estradiol with RE-α promotes periosteal expansion while RE-β inhibits periosteal apposition.

Mice in which ER-α is inactive have thinner bones, but this is not necessarily the case in animals in which ER-β is abrogated.

The idea that β-RE is a negative regulator of periosteal apposition is consistent with the observation that apposition is suppressed in estrogen-replete women and that this inhibition is eliminated in estrogen deficiency.

However, the picture is complicated because in humans, unlike mice, RE-α predominates over RE-β. Thus the antiapoptotic and pro-osteogenic effects of RE-α are inconsistent with the observation of normal premenopause and suppression of periosteal apposition in women or postmenopausal periosteal expansion.

The two receptors may interact in ways that cause different effects when only one is present or when the relative importance of the receptors is gender-specific, with RE-α achieving a more significant impact in the male skeleton. Still, the presence of both is a requirement for apposition in the female frame.

There may also be a more complex relationship in which receptor signaling depends on higher or lower threshold levels of estrogen.

Similarly, the responsiveness of periosteal cells to IGF-I may help explain the stimulating effect of parathyroid hormone (PTH) on periosteal apposition.

Intermittent administration of recombinant human HPT fragment 1-34 (rhHPT [1-34]) is suspected of promoting periosteal apposition, and this phenomenon has partially explained its effect on bone strength.

HPT (1-34) is known to prevent apoptosis of periosteal osteoblasts, partly explaining its effect on cells in the osteogenic layer of the periosteum.

HPT signaling also negatively regulates Sost expression in osteocytes, shown in mice with a constitutively active HPT receptor to increase periosteal bone formation.

Sclerostin, the protein encoded by the Sost gene, downregulates bone formation. Inhibiting Sost expression in osteocytes by HPT increases bone formation on the periosteal surface.


The periosteal membrane provides cells for the growth, development, maturation, adaptation, and repair of our bones throughout our lives.

It is a vital target tissue that maintains our skeletal health and well-being by adapting to our changing developmental, hormonal, and mechanical needs over the many decades of our lives. Although it is often overlooked, it is vital to our skeletal health.